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Cartereau A, Bouchouireb Z, Kaaki S, Héricourt F, Taillebois E, Le Questel JY, Thany SH. Pharmacology and molecular modeling studies of sulfoxaflor, flupyradifurone and neonicotinoids on the human neuronal α7 nicotinic acetylcholine receptor. Toxicol Appl Pharmacol 2024; 492:117123. [PMID: 39393466 DOI: 10.1016/j.taap.2024.117123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/06/2024] [Accepted: 10/06/2024] [Indexed: 10/13/2024]
Abstract
We conducted electrophysiological and molecular docking studies using a heterologous expression system (Xenopus oocytes) to compare the effects of four neonicotinoids (acetamiprid, imidacloprid, clothianidin and thiamethoxam), one sulfoximine, (sulfoxaflor), and one butenolide (flupyradifurone), on human α7 neuronal nicotinic acetylcholine receptors (nAChRs). All neonicotinoids (except thiamethoxam), as well as the recently introduced nAChR competitive modulators, flupyradifurone and sulfoxaflor, appear to be weaker agonists than acetylcholine. Two mutations in loop C (E211N and E211P) and one mutation in loop D (Q79K), known to be involved in the binding properties of neonicotinoids were introduced to the α7 wild type. Interestingly, the acetylcholine and nicotine-evoked activation was not modified in human α7 mutated receptors, but the net charge was enhanced for clothianidin and imidacloprid, respectively. Flupyradifurone responses strongly increased under the Q79K mutation. The molecular docking investigations demonstrated that the orientations and interactions of the ligands considered were in accordance with those observed experimentally. Specifically, the charged fragments of acetylcholine and nicotine, used as reference ligands, and their neonicotinoid homologs were found to be surrounded by aromatic residues, with key interactions with Trp171 and Y210. Furthermore, the molecular docking investigations predicted the water-mediated interaction between the carbonyl oxygen of acetylcholine and the Nsp2 nitrogen of the pyridine ring for nicotine (as well as for the majority of the corresponding neonicotinoid fragments) and main chain NH of L141. The docking scores, extending over a significant range of 6 kcal/mol, showed that most neonicotinoids were poorly stabilized in the α7 nAChR compared to acetylcholine, except sulfoxaflor.
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Affiliation(s)
- Alison Cartereau
- Université d'Orléans, USC INRAE 1328, Laboratoire Physiologie, Ecologie et Environnement (P2E), 1 rue de Chartres, 45067 Orléans, France
| | | | - Sara Kaaki
- Université d'Orléans, USC INRAE 1328, Laboratoire Physiologie, Ecologie et Environnement (P2E), 1 rue de Chartres, 45067 Orléans, France
| | - François Héricourt
- Université d'Orléans, USC INRAE 1328, Laboratoire Physiologie, Ecologie et Environnement (P2E), 1 rue de Chartres, 45067 Orléans, France
| | - Emiliane Taillebois
- Université d'Orléans, USC INRAE 1328, Laboratoire Physiologie, Ecologie et Environnement (P2E), 1 rue de Chartres, 45067 Orléans, France
| | | | - Steeve H Thany
- Université d'Orléans, USC INRAE 1328, Laboratoire Physiologie, Ecologie et Environnement (P2E), 1 rue de Chartres, 45067 Orléans, France; Institut Universitaire de France (IUF), 1 rue Descartes, 75005 Paris, France.
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Becchetti A, Grandi LC, Cerina M, Amadeo A. Nicotinic acetylcholine receptors and epilepsy. Pharmacol Res 2023; 189:106698. [PMID: 36796465 DOI: 10.1016/j.phrs.2023.106698] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/04/2023] [Accepted: 02/13/2023] [Indexed: 02/16/2023]
Abstract
Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype remains difficult. A paradigmatic case is constituted by the epilepsies caused by altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions in mature as well as developing brain. The ascending cholinergic projections exert potent control of forebrain excitability, and wide evidence implicates nAChR dysregulation as both cause and effect of epileptiform activity. First, tonic-clonic seizures are triggered by administration of high doses of nicotinic agonists, whereas non-convulsive doses have kindling effects. Second, sleep-related epilepsy can be caused by mutations on genes encoding nAChR subunits widely expressed in the forebrain (CHRNA4, CHRNB2, CHRNA2). Third, in animal models of acquired epilepsy, complex time-dependent alterations in cholinergic innervation are observed following repeated seizures. Heteromeric nAChRs are central players in epileptogenesis. Evidence is wide for autosomal dominant sleep-related hypermotor epilepsy (ADSHE). Studies of ADSHE-linked nAChR subunits in expression systems suggest that the epileptogenic process is promoted by overactive receptors. Investigation in animal models of ADSHE indicates that expression of mutant nAChRs can lead to lifelong hyperexcitability by altering i) the function of GABAergic populations in the mature neocortex and thalamus, ii) synaptic architecture during synaptogenesis. Understanding the balance of the epileptogenic effects in adult and developing networks is essential to plan rational therapy at different ages. Combining this knowledge with a deeper understanding of the functional and pharmacological properties of individual mutations will advance precision and personalized medicine in nAChR-dependent epilepsy.
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Affiliation(s)
- Andrea Becchetti
- Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy.
| | - Laura Clara Grandi
- Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy.
| | - Marta Cerina
- Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy.
| | - Alida Amadeo
- Department of Biosciences, University of Milano, Via Celoria 26, Milano 20133, Italy.
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Sugisaki E, Fukushima Y, Nakajima N, Aihara T. The dependence of acetylcholine on dynamic changes in the membrane potential and an action potential during spike timing-dependent plasticity induction in the hippocampus. Eur J Neurosci 2022; 56:5972-5986. [PMID: 36164804 DOI: 10.1111/ejn.15832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 09/01/2022] [Accepted: 09/16/2022] [Indexed: 12/29/2022]
Abstract
The hippocampus is an important area for memory encoding and retrieval and is the location of spike timing-dependent plasticity (STDP), a basic phenomenon of learning and memory. STDP is facilitated if acetylcholine (ACh) is released from cholinergic neurons during attentional processes. However, it is unclear how ACh influences postsynaptic changes during STDP induction and determines the STDP magnitude. To address these issues, we obtained patch clamp recordings from CA1 pyramidal neurons to evaluate the postsynaptic changes during stimuli injection in Schaffer collaterals by quantifying baseline amplitudes (i.e., the lowest values elicited by paired pulses comprising STDP stimuli) and action potentials. The results showed that baseline amplitudes were elevated if eserine was applied in the presence of picrotoxin. In addition, muscarinic ACh receptors (mAChRs) contributed more to the baseline amplitude elevation than nicotinic AChRs (nAChRs). Moreover, the magnitude of the STDP depended on the magnitude of the baseline amplitude. However, in the absence of picrotoxin, baseline amplitudes were balanced, regardless of the ACh concentration, resulting in a similar magnitude of the STDP, except under the nAChR alone-activated condition, which showed a larger STDP and lower baseline amplitude induction. This was due to broadened widths of action potentials. These results suggest that activation of mAChRs and nAChRs, which are effective for baseline amplitudes and action potentials, respectively, plays an important role in postsynaptic changes during memory consolidation.
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Affiliation(s)
- Eriko Sugisaki
- Brain Science Institute, Tamagawa University, Tokyo, Japan
| | - Yasuhiro Fukushima
- Brain Science Institute, Tamagawa University, Tokyo, Japan.,Kawasaki University of Medical Welfare, Okayama, Japan
| | - Naoki Nakajima
- Graduated School of Engineering, Tamagawa University, Tokyo, Japan
| | - Takeshi Aihara
- Brain Science Institute, Tamagawa University, Tokyo, Japan
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Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27144527. [PMID: 35889400 PMCID: PMC9318448 DOI: 10.3390/molecules27144527] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/07/2022] [Accepted: 07/09/2022] [Indexed: 11/17/2022]
Abstract
The process of how multimeric transmembrane proteins fold and assemble in the endoplasmic reticulum is not well understood. The alpha7 nicotinic receptor (α7 nAChR) is a good model for multimeric protein assembly since it has at least two independent and specialized chaperones: Resistance to Inhibitors of Cholinesterase 3 (RIC-3) and Nicotinic Acetylcholine Receptor Regulator (NACHO). Recent cryo-EM and NMR data revealed structural features of α7 nAChRs. A ser-ala-pro (SAP) motif precedes a structurally important but unique "latch" helix in α7 nAChRs. A sampling of α7 sequences suggests the SAP motif is conserved from C. elegans to humans, but the latch sequence is only conserved in vertebrates. How RIC-3 and NACHO facilitate receptor subunits folding into their final pentameric configuration is not known. The artificial intelligence program AlphaFold2 recently predicted structures for NACHO and RIC-3. NACHO is highly conserved in sequence and structure across species, but RIC-3 is not. This review ponders how different intrinsically disordered RIC-3 isoforms from C. elegans to humans interact with α7 nAChR subunits despite having little sequence homology across RIC-3 species. Two models from the literature about how RIC-3 assists α7 nAChR assembly are evaluated considering recent structural information about the receptor and its chaperones.
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Hellmer CB, Hall LM, Bohl JM, Sharpe ZJ, Smith RG, Ichinose T. Cholinergic feedback to bipolar cells contributes to motion detection in the mouse retina. Cell Rep 2021; 37:110106. [PMID: 34910920 PMCID: PMC8793255 DOI: 10.1016/j.celrep.2021.110106] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 08/11/2021] [Accepted: 11/16/2021] [Indexed: 11/25/2022] Open
Abstract
Retinal bipolar cells are second-order neurons that transmit basic features of the visual scene to postsynaptic partners. However, their contribution to motion detection has not been fully appreciated. Here, we demonstrate that cholinergic feedback from starburst amacrine cells (SACs) to certain presynaptic bipolar cells via alpha-7 nicotinic acetylcholine receptors (α7-nAChRs) promotes direction-selective signaling. Patch clamp recordings reveal that distinct bipolar cell types making synapses at proximal SAC dendrites also express α7-nAChRs, producing directionally skewed excitatory inputs. Asymmetric SAC excitation contributes to motion detection in On-Off direction-selective ganglion cells (On-Off DSGCs), predicted by computational modeling of SAC dendrites and supported by patch clamp recordings from On-Off DSGCs when bipolar cell α7-nAChRs is eliminated pharmacologically or by conditional knockout. Altogether, these results show that cholinergic feedback to bipolar cells enhances direction-selective signaling in postsynaptic SACs and DSGCs, illustrating how bipolar cells provide a scaffold for postsynaptic microcircuits to cooperatively enhance retinal motion detection.
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Affiliation(s)
- Chase B Hellmer
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; Present address: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40202, USA
| | - Leo M Hall
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; Present address: Department of Internal Medicine, St. Mary Mercy Livonia Hospital, Livonia, MI 48154, USA
| | - Jeremy M Bohl
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Zachary J Sharpe
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Robert G Smith
- Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tomomi Ichinose
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
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Lipovsek M, Marcovich I, Elgoyhen AB. The Hair Cell α9α10 Nicotinic Acetylcholine Receptor: Odd Cousin in an Old Family. Front Cell Neurosci 2021; 15:785265. [PMID: 34867208 PMCID: PMC8634148 DOI: 10.3389/fncel.2021.785265] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 10/25/2021] [Indexed: 11/13/2022] Open
Abstract
Nicotinic acetylcholine receptors (nAChRs) are a subfamily of pentameric ligand-gated ion channels with members identified in most eumetazoan clades. In vertebrates, they are divided into three subgroups, according to their main tissue of expression: neuronal, muscle and hair cell nAChRs. Each receptor subtype is composed of different subunits, encoded by paralogous genes. The latest to be identified are the α9 and α10 subunits, expressed in the mechanosensory hair cells of the inner ear and the lateral line, where they mediate efferent modulation. α9α10 nAChRs are the most divergent amongst all nicotinic receptors, showing marked differences in their degree of sequence conservation, their expression pattern, their subunit co-assembly rules and, most importantly, their functional properties. Here, we review recent advances in the understanding of the structure and evolution of nAChRs. We discuss the functional consequences of sequence divergence and conservation, with special emphasis on the hair cell α9α10 receptor, a seemingly distant cousin of neuronal and muscle nicotinic receptors. Finally, we highlight potential links between the evolution of the octavolateral system and the extreme divergence of vertebrate α9α10 receptors.
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Affiliation(s)
- Marcela Lipovsek
- Ear Institute, Faculty of Brain Sciences, University College London, London, United Kingdom
| | - Irina Marcovich
- Departments of Otolaryngology & Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Ana Belén Elgoyhen
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres" (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Vallés AS, Barrantes FJ. Dendritic spine membrane proteome and its alterations in autistic spectrum disorder. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 128:435-474. [PMID: 35034726 DOI: 10.1016/bs.apcsb.2021.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Dendritic spines are small protrusions stemming from the dendritic shaft that constitute the primary specialization for receiving and processing excitatory neurotransmission in brain synapses. The disruption of dendritic spine function in several neurological and neuropsychiatric diseases leads to severe information-processing deficits with impairments in neuronal connectivity and plasticity. Spine dysregulation is usually accompanied by morphological alterations to spine shape, size and/or number that may occur at early pathophysiological stages and not necessarily be reflected in clinical manifestations. Autism spectrum disorder (ASD) is one such group of diseases involving changes in neuronal connectivity and abnormal morphology of dendritic spines on postsynaptic neurons. These alterations at the subcellular level correlate with molecular changes in the spine proteome, with alterations in the copy number, topography, or in severe cases in the phenotype of the molecular components, predominantly of those proteins involved in spine recognition and adhesion, reflected in abnormally short lifetimes of the synapse and compensatory increases in synaptic connections. Since cholinergic neurotransmission participates in the regulation of cognitive function (attention, memory, learning processes, cognitive flexibility, social interactions) brain acetylcholine receptors are likely to play an important role in the dysfunctional synapses in ASD, either directly or indirectly via the modulatory functions exerted on other neurotransmitter receptor proteins and spine-resident proteins.
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Affiliation(s)
- Ana Sofía Vallés
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (UNS-CONICET), Bahía Blanca, Argentina
| | - Francisco J Barrantes
- Instituto de Investigaciones Biomédicas (BIOMED), UCA-CONICET, Buenos Aires, Argentina.
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Temporal regulation of nicotinic acetylcholine receptor subunits supports central cholinergic synapse development in Drosophila. Proc Natl Acad Sci U S A 2021; 118:2004685118. [PMID: 34074746 DOI: 10.1073/pnas.2004685118] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The construction and maturation of the postsynaptic apparatus are crucial for synapse and dendrite development. The fundamental mechanisms underlying these processes are most often studied in glutamatergic central synapses in vertebrates. Whether the same principles apply to excitatory cholinergic synapses, such as those found in the insect central nervous system, is not known. To address this question, we investigated a group of projection neurons in the Drosophila larval visual system, the ventral lateral neurons (LNvs), and identified nAchRα1 (Dα1) and nAchRα6 (Dα6) as the main functional nicotinic acetylcholine receptor (nAchR) subunits in the larval LNvs. Using morphological analyses and calcium imaging studies, we demonstrated critical roles of these two subunits in supporting dendrite morphogenesis and synaptic transmission. Furthermore, our RNA sequencing analyses and endogenous tagging approach identified distinct transcriptional controls over the two subunits in the LNvs, which led to the up-regulation of Dα1 and down-regulation of Dα6 during larval development as well as to an activity-dependent suppression of Dα1 Additional functional analyses of synapse formation and dendrite dynamics further revealed a close association between the temporal regulation of individual nAchR subunits and their sequential requirements during the cholinergic synapse maturation. Together, our findings support transcriptional control of nAchR subunits as a core element of developmental and activity-dependent regulation of central cholinergic synapses.
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Hou YJ, Zheng X, Zhong HM, Chen F, Yan GY, Cai KC. Structural dynamics of amyloid β peptide binding to acetylcholine receptor and virtual screening for effective inhibitors. CHINESE J CHEM PHYS 2021. [DOI: 10.1063/1674-0068/cjcp2008150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
- Yan-jun Hou
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
- Fujian Provincial Key Laboratory of Featured Biochemical and Chemical Materials, Ningde Normal University, Ningde 352100, China
- Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen 361005, China
| | - Xuan Zheng
- Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Hong-mei Zhong
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
- Fujian Provincial Key Laboratory of Featured Biochemical and Chemical Materials, Ningde Normal University, Ningde 352100, China
- Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen 361005, China
| | - Feng Chen
- Fujian Provincial Key Laboratory of Featured Biochemical and Chemical Materials, Ningde Normal University, Ningde 352100, China
| | - Gui-yang Yan
- Fujian Provincial Key Laboratory of Featured Biochemical and Chemical Materials, Ningde Normal University, Ningde 352100, China
| | - Kai-cong Cai
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
- Fujian Provincial Key Laboratory of Featured Biochemical and Chemical Materials, Ningde Normal University, Ningde 352100, China
- Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen 361005, China
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Structure and gating mechanism of the α7 nicotinic acetylcholine receptor. Cell 2021; 184:2121-2134.e13. [PMID: 33735609 DOI: 10.1016/j.cell.2021.02.049] [Citation(s) in RCA: 167] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/13/2021] [Accepted: 02/22/2021] [Indexed: 12/13/2022]
Abstract
The α7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and in the cholinergic inflammatory pathway. This ligand-gated ion channel assembles as a homopentamer, is exceptionally permeable to Ca2+, and desensitizes faster than any other Cys-loop receptor. The α7 receptor has served as a prototype for the Cys-loop superfamily yet has proven refractory to structural analysis. We present cryo-EM structures of the human α7 nicotinic receptor in a lipidic environment in resting, activated, and desensitized states, illuminating the principal steps in the gating cycle. The structures also reveal elements that contribute to its function, including a C-terminal latch that is permissive for channel opening, and an anionic ring in the extracellular vestibule that contributes to its high conductance and calcium permeability. Comparisons among the α7 structures provide a foundation for mapping the gating cycle and reveal divergence in gating mechanisms in the Cys-loop receptor superfamily.
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11
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Xu ZQ, Zhang WJ, Su DF, Zhang GQ, Miao CY. Cellular responses and functions of α7 nicotinic acetylcholine receptor activation in the brain: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:509. [PMID: 33850906 PMCID: PMC8039675 DOI: 10.21037/atm-21-273] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The α7 nicotinic acetylcholine receptor (α7nAChR) has been studied for many years since its discovery. Although many functions and characteristics of brain α7nAChR are widely understood, much remains to be elucidated. The α7nAChR is widely expressed in the central nervous system, not only in neurons but also in astrocytes, microglia, and endothelial cells. α7nAChR can be activated by endogenous agonist like acetylcholine or exogenous agonists like nicotine and PNU282987. Its agonists can be divided into selective agonists and non-selective agonists. The activation of α7nAChR results in a series of physiological processes which have both short-term and long-term effects on cells, for example, calcium influx, neurotransmitter release, synaptic plasticity, and excitatory transmission. It also induces other downstream events, such as inflammation, autophagy, necrosis, transcription, and apoptosis. The cellular responses to α7nAChR activation vary according to cell types and conditions. For example, α7nAChR activation in pyramidal neurons leads to long-term potentiation, while α7nAChR activation in GABAergic interneurons leads to long-term depression. Studies have also shown some contradictory phenomena, which requires further study for clarification. Herein, the cellular responses of α7nAChR activation are summarized, and the functions of α7nAChR in neurons and non-neuronal cells are discussed. We also summarized contradictory conclusions to show where we stand and where to go for future studies.
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Affiliation(s)
- Zhe-Qi Xu
- Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai, China.,Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Wen-Jun Zhang
- Department of Neurology, Dongying People's Hospital, Dongying, China
| | - Ding-Feng Su
- Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Guo-Qing Zhang
- Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Chao-Yu Miao
- Department of Pharmacology, Second Military Medical University/Naval Medical University, Shanghai, China
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Miller DR, Khoshbouei H, Garai S, Cantwell LN, Stokes C, Thakur G, Papke RL. Allosterically Potentiated α7 Nicotinic Acetylcholine Receptors: Reduced Calcium Permeability and Current-Independent Control of Intracellular Calcium. Mol Pharmacol 2020; 98:695-709. [PMID: 33020143 PMCID: PMC7662531 DOI: 10.1124/molpharm.120.000012] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 09/10/2020] [Indexed: 11/22/2022] Open
Abstract
The currents of α7 nicotinic acetylcholine receptors activated by acetylcholine (ACh) are brief. The channel has high permeability to calcium relative to monovalent cations and shows inward rectification. It has been previously noted that in the presence of positive allosteric modulators (PAMs), currents through the channels of α7 receptors differ from normal α7 currents both in sensitivity to specific channel blockers and their current-voltage (I-V) relationships, no longer showing inward rectification. Linear I-V functions are often associated with channels lacking calcium permeability, so we measured the I-V functions of α7 receptors activated by ACh when PAMs were bound to the allosteric binding site in the transmembrane domain. Currents were recorded in chloride-free Ringer's solution with low or high concentrations of extracellular calcium to determine the magnitude of the reversal potential shift in the two conditions as well as the I-V relationships. ACh-evoked currents potentiated by the allosteric agonist-PAMs (ago-PAMs) (3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (GAT107) and 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propenamide (B-973B) showed reduced inward rectification and calcium-dependent reversal potential shifts decreased by 80%, and 50%, respectively, compared with currents activated by ACh alone, indicative of reduced calcium permeability. Currents potentiated by 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide were also linear and showed no calcium-dependent reversal potential shifts. The ago-PAMs GAT-107 and B-973B stimulated increases in intracellular calcium in stably transfected HEK293 cells. However, these calcium signals were delayed relative to channel activation produced by these agents and were insensitive to the channel blocker mecamylamine. Our results indicate that, although allosterically activated α7 nicotinic ACh receptor may affect intracellular calcium levels, such effects are not likely due to large channel-dependent calcium influx. SIGNIFICANCE STATEMENT: Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor can increase channel activation by two or more orders of magnitude, raising the concern that, due to the relatively high calcium permeability of α7 receptors activated by acetylcholine alone, such efficacious PAMs may have cytotoxic side effects. We show that PAMs alter the ion conduction pathway and, in general, reduce the calcium permeability of the channels. This supports the hypothesis that α7 effects on intracellular calcium may be independent of channel-mediated calcium influx.
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Affiliation(s)
- Douglas R Miller
- Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
| | - Habibeh Khoshbouei
- Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
| | - Sumanta Garai
- Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
| | - Lucas N Cantwell
- Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
| | - Clare Stokes
- Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
| | - Ganesh Thakur
- Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
| | - Roger L Papke
- Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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13
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Cottone G, Chiodo L, Maragliano L. Thermodynamics and Kinetics of Ion Permeation in Wild-Type and Mutated Open Active Conformation of the Human α7 Nicotinic Receptor. J Chem Inf Model 2020; 60:5045-5056. [PMID: 32803965 PMCID: PMC8011927 DOI: 10.1021/acs.jcim.0c00549] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
![]()
Molecular
studies of human pentameric ligand-gated ion channels
(LGICs) expressed in neurons and at neuromuscular junctions are of
utmost importance in the development of therapeutic strategies for
neurological disorders. We focus here on the nicotinic acetylcholine
receptor nAChR-α7, a homopentameric channel widely expressed
in the human brain, with a proven role in a wide spectrum of disorders
including schizophrenia and Alzheimer’s disease. By exploiting
an all-atom structural model of the full (transmembrane and extracellular)
protein in the open, agonist-bound conformation we recently developed,
we evaluate the free energy and the mean first passage time of single-ion
permeation using molecular dynamics simulations and the milestoning
method with Voronoi tessellation. The results for the wild-type channel
provide the first available mapping of the potential of mean force
in the full-length α7 nAChR, reveal its expected cationic nature,
and are in good agreement with simulation data for other channels
of the LGIC family and with experimental data on nAChRs. We then investigate
the role of a specific mutation directly related to ion selectivity
in LGICs, the E-1′ → A-1′ substitution at the
cytoplasmatic selectivity filter. We find that the mutation strongly
affects sodium and chloride permeation in opposite directions, leading
to a complete inversion of selectivity, at variance with the limited
experimental results available that classify this mutant as cationic.
We thus provide structural determinants for the observed cationic-to-anionic
inversion, revealing a key role of the protonation state of residue
rings far from the mutation, in the proximity of the hydrophobic channel
gate.
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Affiliation(s)
- Grazia Cottone
- Department of Physics and Chemistry-Emilio Segrè, University of Palermo, Viale delle Scienze Ed. 17, 90128 Palermo, Italy
| | - Letizia Chiodo
- Department of Engineering, Campus Bio-Medico University of Rome, Via Á. del Portillo 21, 00128 Rome, Italy
| | - Luca Maragliano
- Center for Synaptic Neuroscience and Technology (NSYN@UniGe), Istituto Italiano di Tecnologia, Largo Rosanna Benzi, 10, 16132 Genova, Italy.,IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132 Genova, Italy
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14
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Jokura K, Nishino JM, Ogasawara M, Nishino A. An α7-related nicotinic acetylcholine receptor mediates the ciliary arrest response in pharyngeal gill slits of Ciona. J Exp Biol 2020; 223:jeb209320. [PMID: 32220975 DOI: 10.1242/jeb.209320] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 03/18/2020] [Indexed: 11/20/2022]
Abstract
Ciliary movement is a fundamental process to support animal life, and the movement pattern may be altered in response to external stimuli under the control of nervous systems. Juvenile and adult ascidians have ciliary arrays around their pharyngeal gill slits (stigmata), and continuous beating is interrupted for seconds by mechanical stimuli on other parts of the body. Although it has been suggested that neural transmission to evoke ciliary arrest is cholinergic, its molecular basis has not yet been elucidated in detail. Here, we attempted to clarify the molecular mechanisms underlying this neurociliary transmission in the model ascidian Ciona Acetylcholinesterase histochemical staining showed strong signals on the laterodistal ciliated cells of stigmata, hereafter referred to as trapezial cells. The direct administration of acetylcholine (ACh) and other agonists of nicotinic ACh receptors (nAChRs) onto ciliated cells reliably evoked ciliary arrest that persisted for seconds in a dose-dependent manner. While the Ciona genome encodes ten nAChRs, only one of these called nAChR-A7/8-1, a relative of vertebrate α7 nAChRs, was found to be expressed by trapezial cells. Exogenously expressed nAChR-A7/8-1 on Xenopus oocytes responded to ACh and other agonists with consistent pharmacological traits to those observed in vivo Further efforts to examine signaling downstream of this receptor revealed that an inhibitor of phospholipase C (PLC) hampered ACh-induced ciliary arrest. We propose that homomeric α7-related nAChR-A7/8-1 mediates neurociliary transmission in Ciona stigmata to elicit persistent ciliary arrest by recruiting intracellular Ca2+ signaling.
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Affiliation(s)
- Kei Jokura
- Department of Biology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki 036-8561, Japan
- Division of Marine Molecular Biology, Shimoda Marine Research Center, University of Tsukuba, Shimoda 415-0025, Japan
| | - Junko M Nishino
- Department of Bioresources Science, United Graduate School of Agricultural Sciences, Iwate University, Hirosaki 036-8561, Japan
| | - Michio Ogasawara
- Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan
| | - Atsuo Nishino
- Department of Biology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki 036-8561, Japan
- Department of Bioresources Science, United Graduate School of Agricultural Sciences, Iwate University, Hirosaki 036-8561, Japan
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15
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Houchat JN, Cartereau A, Le Mauff A, Taillebois E, Thany SH. An Overview on the Effect of Neonicotinoid Insecticides on Mammalian Cholinergic Functions through the Activation of Neuronal Nicotinic Acetylcholine Receptors. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17093222. [PMID: 32384754 PMCID: PMC7246883 DOI: 10.3390/ijerph17093222] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 01/04/2023]
Abstract
Neonicotinoid insecticides are used worldwide and have been demonstrated as toxic to beneficial insects such as honeybees. Their effectiveness is predominantly attributed to their high affinity for insect neuronal nicotinic acetylcholine receptors (nAChRs). Mammalian neuronal nAChRs are of major importance because cholinergic synaptic transmission plays a key role in rapid neurotransmission, learning and memory processes, and neurodegenerative diseases. Because of the low agonist effects of neonicotinoid insecticides on mammalian neuronal nAChRs, it has been suggested that they are relatively safe for mammals, including humans. However, several lines of evidence have demonstrated that neonicotinoid insecticides can modulate cholinergic functions through neuronal nAChRs. Major studies on the influence of neonicotinoid insecticides on cholinergic functions have been conducted using nicotine low-affinity homomeric α7 and high-affinity heteromeric α4β2 receptors, as they are the most abundant in the nervous system. It has been found that the neonicotinoids thiamethoxam and clothianidin can activate the release of dopamine in rat striatum. In some contexts, such as neurodegenerative diseases, they can disturb the neuronal distribution or induce oxidative stress, leading to neurotoxicity. This review highlights recent studies on the mode of action of neonicotinoid insecticides on mammalian neuronal nAChRs and cholinergic functions.
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16
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Wang X, Daley C, Gakhar V, Lange HS, Vardigan JD, Pearson M, Zhou X, Warren L, Miller CO, Belden M, Harvey AJ, Grishin AA, Coles CJ, O'Connor SM, Thomson F, Duffy JL, Bell IM, Uslaner JM. Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor-Positive Allosteric Modulator BNC375. J Pharmacol Exp Ther 2020; 373:311-324. [PMID: 32094294 DOI: 10.1124/jpet.119.263483] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/17/2020] [Indexed: 12/28/2022] Open
Abstract
Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.
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Affiliation(s)
- Xiaohai Wang
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Christopher Daley
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Vanita Gakhar
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Henry S Lange
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Joshua D Vardigan
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Michelle Pearson
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Xiaoping Zhou
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Lee Warren
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Corin O Miller
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Michelle Belden
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Andrew J Harvey
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Anton A Grishin
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Carolyn J Coles
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Susan M O'Connor
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Fiona Thomson
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Joseph L Duffy
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Ian M Bell
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
| | - Jason M Uslaner
- Merck Research Laboratories, Merck & Co., Inc., Kenilworth, New Jersey (X.W., C.D., V.G., H.S.L., J.D.V., M.P., X.Z., L.W., C.O.M., M.B., F.T., J.L.D., I.M.B., J.M.U.) and Bionomics Limited, Thebarton, Australia (A.J.H., A.A.G., C.J.C., S.M.O.)
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17
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Bertrand D, Wallace TL. A Review of the Cholinergic System and Therapeutic Approaches to Treat Brain Disorders. Curr Top Behav Neurosci 2020; 45:1-28. [PMID: 32451956 DOI: 10.1007/7854_2020_141] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Since its identification over a hundred years ago, the neurotransmitter acetylcholine (ACh) has proven to play an essential role in supporting many diverse functions. Some well-characterized functions include: chemical transmission at the neuromuscular junction; autonomic function in the peripheral nervous system; and, sustained attention, sleep/wake regulation, and learning and memory within the central nervous system. Within the brain, major cholinergic projection pathways from the basal forebrain and the brainstem support these centrally mediated processes, and dysregulation of the cholinergic system is implicated in cognitive decline associated with aging and dementias including Alzheimer's disease. ACh exerts its effects by binding to two different membrane-bound receptor classes: (1) G‑protein coupled muscarinic acetylcholine receptors (mAChRs), and (2) ligand-gated nicotinic acetylcholine receptors (nAChRs). These receptor systems are described in detail within this chapter along with discussion on the successes and failures of synthetic ligands designed to selectively target receptor subtypes for treating brain disorders. New molecular approaches and advances in our understanding of the target biology combined with opportunities to re-purpose existing cholinergic drugs for new indications continue to highlight the exciting opportunities for modulating this system for therapeutic purposes.
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18
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Wang X, Bell IM, Uslaner JM. Activators of α7 nAChR as Potential Therapeutics for Cognitive Impairment. Curr Top Behav Neurosci 2020; 45:209-245. [PMID: 32451955 DOI: 10.1007/7854_2020_140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The α7 nicotinic acetylcholine receptor (nAChR) is a promising target for the treatment of cognitive deficits associated with psychiatric and neurological disorders, including schizophrenia and Alzheimer's disease (AD). Several α7 nAChR agonists and positive allosteric modulators (PAMs) have demonstrated procognitive effects in preclinical models and early clinical trials. However, despite intense research efforts in the pharmaceutical industry and academia, none of the α7 nAChR ligands has been approved for clinical use. This chapter will focus on the α7 nAChR ligands that have advanced to clinical studies and explore the reasons why these agents have not met with unequivocal clinical success.
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Affiliation(s)
- Xiaohai Wang
- Department of Neuroscience Research, Merck & Co. Inc., West Point, PA, USA
| | - Ian M Bell
- Department of Discovery Chemistry, Merck & Co. Inc., West Point, PA, USA
| | - Jason M Uslaner
- Department of Neuroscience Research, Merck & Co. Inc., West Point, PA, USA.
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19
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Hahm ET, Nagaraja RY, Waro G, Tsunoda S. Cholinergic Homeostatic Synaptic Plasticity Drives the Progression of Aβ-Induced Changes in Neural Activity. Cell Rep 2019; 24:342-354. [PMID: 29996096 DOI: 10.1016/j.celrep.2018.06.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 04/03/2018] [Accepted: 06/06/2018] [Indexed: 12/23/2022] Open
Abstract
Homeostatic synaptic plasticity (HSP) is the ability of neurons to exert compensatory changes in response to altered neural activity. How pathologically induced activity changes are intertwined with HSP mechanisms is unclear. We show that, in cholinergic neurons from Drosophila, beta-amyloid (Aβ) peptides Aβ40 and Aβ42 both induce an increase in spontaneous activity. In a transgenic line expressing Aβ42, we observe that this early increase in spontaneous activity is followed by a dramatic reduction in spontaneous events, a progression that has been suggested to occur in cholinergic brain regions of mammalian models of Alzheimer's disease. We present evidence that the early enhancement in synaptic activity is mediated by the Drosophila α7 nicotinic acetylcholine receptor (nAChR) and that, later, Aβ42-induced inhibition of synaptic events is a consequence of Dα7-dependent HSP mechanisms induced by earlier hyperactivity. Thus, while HSP may initially be an adaptive response, it may also drive maladaptive changes and downstream pathologies.
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Affiliation(s)
- Eu-Teum Hahm
- Department of Biomedical Sciences, Colorado State University, 1617 Campus Delivery, Fort Collins, CO 80523, USA
| | - Raghavendra Y Nagaraja
- Department of Biomedical Sciences, Colorado State University, 1617 Campus Delivery, Fort Collins, CO 80523, USA
| | - Girma Waro
- Department of Biomedical Sciences, Colorado State University, 1617 Campus Delivery, Fort Collins, CO 80523, USA
| | - Susan Tsunoda
- Department of Biomedical Sciences, Colorado State University, 1617 Campus Delivery, Fort Collins, CO 80523, USA.
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20
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Suresh A, Hung A. Structural effects of divalent calcium cations on the α7 nicotinic acetylcholine receptor: A molecular dynamics simulation study. Proteins 2019; 87:992-1005. [PMID: 31228282 DOI: 10.1002/prot.25761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 05/27/2019] [Accepted: 06/15/2019] [Indexed: 12/11/2022]
Abstract
The α7 subtype of neuronal nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel protein that is vital to various neurological functions, including modulation of neurotransmitter release. A relatively high concentration of extracellular Ca2+ in the neuronal environment is likely to exert substantial structural and functional influence on nAChRs, which may affect their interactions with agonists and antagonists. In this work, we employed atomistic molecular dynamics (MD) simulations to examine the effects of elevated Ca2+ on the structure and dynamics of α7 nAChR embedded in a model phospholipid bilayer. Our results suggest that the presence of Ca2+ in the α7 nAChR environment results in closure of loop C-in the extracellular ligand-binding domain, a motion normally associated with agonist binding and receptor activation. Elevated Ca2+ also alters the conformation of key regions of the receptor, including the inter-helical loops, pore-lining helices and the "gate" residues, and causes partial channel opening in the absence of an agonist, leading to an attendant reduction in the free energy of Ca2+ permeation through the pore as elucidated by umbrella sampling simulations. Overall, the structural and permeability changes in α7 nAChR suggest that elevated Ca2+ induces a partially activated receptor state that is distinct from both the resting and the agonist-activated states. These results are consistent with the notion that divalent ions can serve as a potentiator of nAChRs, resulting in a higher rate of receptor activation (and subsequent desensitization) in the presence of agonists, with possible implications for diseases involving calcium dysregulation.
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Affiliation(s)
- Abishek Suresh
- School of Science, RMIT University, Melbourne, Victoria, Australia
| | - Andrew Hung
- School of Science, RMIT University, Melbourne, Victoria, Australia
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21
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Sawamura N, Ju Y, Asahi T. Cholinergic receptor, nicotinic, alpha 7 as a target molecule of Arctic mutant amyloid β. Neural Regen Res 2018; 13:1360-1361. [PMID: 30106044 PMCID: PMC6108216 DOI: 10.4103/1673-5374.235238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Naoya Sawamura
- Faculty of Science and Engineering; Research Organization for Nano & Life Innovation, Waseda University, Tokyo, Japan
| | - Ye Ju
- Faculty of Science and Engineering, Waseda University, Tokyo, Japan
| | - Toru Asahi
- Faculty of Science and Engineering; Research Organization for Nano & Life Innovation, Waseda University, Tokyo, Japan
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22
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The current agonists and positive allosteric modulators of α7 nAChR for CNS indications in clinical trials. Acta Pharm Sin B 2017; 7:611-622. [PMID: 29159020 PMCID: PMC5687317 DOI: 10.1016/j.apsb.2017.09.001] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 08/02/2017] [Accepted: 08/25/2017] [Indexed: 01/06/2023] Open
Abstract
The alpha-7 nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca2+-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of α7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of α7 nAChR modulators have been reported and several of them have advanced into clinical trials. In this brief review, we outline recent progress made in understanding the role of the α7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of α7 nAChR modulators used in clinical trials.
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Key Words
- 5-CSRTT, five-choice serial reaction time task
- 5-HT, serotonin
- ACh, acetylcholine
- AD, Alzheimer's disease
- ADHD, attention deficit hyperactivity disorder
- Acetylcholine
- Alpha7
- Alzheimer's disease
- Aβ, amyloid-β peptide
- CNS, central nervous system
- DMTS, delayed matching-to-sample
- ECD, extracellular domain
- GABA, γ-aminobutyric acid
- Ion channel
- MLA, methyllycaconitine
- NOR, novel object recognition
- PAMs, positive allosteric modulators
- PCP, neonatal phencyclidine
- PD, Parkinson's disease
- PPI, prepulse inhibition
- Positive allosteric modulators
- SAR, structure–activity relationship
- Schizophrenia
- TMD, transmembrane domains
- nAChR
- nAChR, nicotinic acetylcholine receptor
- α-Btx, α-bungarotoxin
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Sakata K, Overacre AE. Promoter IV-BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments. J Neurochem 2017; 143:49-64. [PMID: 28722769 DOI: 10.1111/jnc.14129] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/05/2017] [Accepted: 07/13/2017] [Indexed: 11/29/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity-dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity-dependent BDNF via promoter IV (KIV) and control wild-type mice. Quantitative RT-PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex of KIV mice compared to wild-type mice. Three-week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment (EET) did not affect the altered expression of these genes except that EET increased CHRNA5 levels only in KIV frontal cortex. EET also increased levels of CHRNA7, CHT, and ChAT, again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up-regulated hippocampal CHRM2 and frontal cortex CHRM5 in both genotypes, and frontal cortex CHRNA7 only in KIV mice. To the best of our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA5, CHRM2, and CHRM5. Our results suggest that promoter IV-BDNF deficiency - which occurs under chronic stress - causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA5, CHRM2, and CHRM5 may become an alternative strategy to reverse these BDNF-linked cholinergic dysfunctions.
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Affiliation(s)
- Kazuko Sakata
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Abigail E Overacre
- Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA
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Fucile S. The Distribution of Charged Amino Acid Residues and the Ca 2+ Permeability of Nicotinic Acetylcholine Receptors: A Predictive Model. Front Mol Neurosci 2017; 10:155. [PMID: 28611586 PMCID: PMC5447003 DOI: 10.3389/fnmol.2017.00155] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/08/2017] [Indexed: 11/13/2022] Open
Abstract
Nicotinic acetylcholine receptors (nAChRs) are cation-selective ligand-gated ion channels exhibiting variable Ca2+ permeability depending on their subunit composition. The Ca2+ permeability is a crucial functional parameter to understand the physiological role of nAChRs, in particular considering their ability to modulate Ca2+-dependent processes such as neurotransmitter release. The rings of extracellular and intracellular charged amino acid residues adjacent to the pore-lining TM2 transmembrane segment have been shown to play a key role in the cation selectivity of these receptor channels, but to date a quantitative relationship between these structural determinants and the Ca2+ permeability of nAChRs is lacking. In the last years the Ca2+ permeability of several nAChR subtypes has been experimentally evaluated, in terms of fractional Ca2+ current (Pf, i.e., the percentage of the total current carried by Ca2+ ions). In the present study, the available Pf-values of nAChRs are used to build a simplified modular model describing the contribution of the charged residues in defined regions flanking TM2 to the selectivity filter controlling Ca2+ influx. This model allows to predict the currently unknown Pf-values of existing nAChRs, as well as the hypothetical Ca2+ permeability of subunit combinations not able to assemble into functional receptors. In particular, basing on the amino acid sequences, a Pf > 50% would be associated with homomeric nAChRs composed by different α subunits, excluding α7, α9, and α10. Furthermore, according to the model, human α7β2 receptors should have Pf-values ranging from 3.6% (4:1 ratio) to 0.1% (1:4 ratio), much lower than the 11.4% of homomeric α7 nAChR. These results help to understand the evolution and the function of the large diversity of the nicotinic receptor family.
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Affiliation(s)
- Sergio Fucile
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza Università di RomaRome, Italy.,Molecular Pathology, Istituto Neurologico Mediterraneo (IRCCS), Parco TecnologicoPozzilli, Italy
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25
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Acetylcholine released from T cells regulates intracellular Ca 2+, IL-2 secretion and T cell proliferation through nicotinic acetylcholine receptor. Life Sci 2016; 172:13-18. [PMID: 28025040 DOI: 10.1016/j.lfs.2016.12.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 11/23/2022]
Abstract
AIMS T lymphocytes synthesize acetylcholine (ACh) and express muscarinic and nicotinic ACh receptors (mAChR and nAChR, respectively) responsible for increases in the intracellular Ca2+ concentration ([Ca2+]i). Our aim in the present study was to assess whether autocrine ACh released from T lymphocytes regulates their physiological functions. MAIN METHODS MOLT-3 human leukemic cell line and murine splenocytes were loaded with fura-2 to monitor [Ca2+]i changes in the absence or presence of several AChR antagonists, including mecamylamine, methyllycaconitine and scopolamine. Real-time PCR and ELISA were performed to measure interleukin-2 (IL-2) mRNA and protein levels. KEY FINDINGS T lymphocytes constitutively produce sufficient amounts of ACh to elicit autocrine changes in [Ca2+]i. These autocrine ACh-evoked [Ca2+]i transients were mediated by nAChRs and then influx of extracellular Ca2+. Mecamylamine, a nAChR inhibitor, suppressed not only these [Ca2+]i transients, but also IL-2 release and T cell proliferation. SIGNIFICANCE Here, we confirmed that T lymphocytes utilize ACh as a tool to interact with each other and that autocrine ACh-activated nAChRs are involved in cytokine release and cell proliferation. These findings suggest the possibility that nAChR agonists and antagonists and smoking are able to modulate immune function, which in turn suggests the therapeutic potential of immune activation or suppression using nAChR agonists or antagonists.
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Sugisaki E, Fukushima Y, Fujii S, Yamazaki Y, Aihara T. The effect of coactivation of muscarinic and nicotinic acetylcholine receptors on LTD in the hippocampal CA1 network. Brain Res 2016; 1649:44-52. [PMID: 27545666 DOI: 10.1016/j.brainres.2016.08.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 08/14/2016] [Accepted: 08/18/2016] [Indexed: 11/30/2022]
Abstract
The neuromodulator acetylcholine (ACh) is considered to have a crucial effect on sensory inputs in the process of learning and memory, and ACh activates muscarinic (mAChR) and nicotinic (nAChR) acetylcholine receptors. Meanwhile in a hippocampal CA1 network including inhibitory connections, long-term potentiation (LTP) or long-term depression (LTD) is induced by the application of positive timing of the spike timing-dependent plasticity (STDP) protocol, while LTD is induced by negative timing protocol. In the previous study, the influence of ACh on LTD induced by the negative timing protocol application in the interneuron-blocked CA1 network was reported. However, the responsibility of mAChR and nAChR on pyramidal neuron and interneuron on STDP induction is still unclear. In order to clarify the role of AChRs in LTD, positive or negative timing protocol was applied in the interneuron-activated CA1 network in the presence of eserine. Consequently, the LTD induced by the positive timing protocol was switched to LTP, and the LTD by negative timing protocol was shifted toward potentiation when ACh was effective. The STDP facilitation was more effectively brought by mAChR activation on pyramidal neuron than nAChR, while mAChR on interneuron had a potential to down regulate the facilitation. These findings suggest that the direction (LTD/LTP) of STDP is determined by the activation of mAChR not only on pyramidal neuron but also on interneuron, and the magnitude of STDP is sensitively fine-tuned by nAChR. Therefore, the modulation of synaptic plasticity induced by the coactivation of mAChR and nAChR might be an important stage in integrating ACh and sensory inputs in the hippocampal CA1 network.
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Affiliation(s)
- Eriko Sugisaki
- College of Engineering, Tamagawa University, 6-1-1 Tamagawagakuen, Machida, Tokyo 194-8610, Japan; Brain Science Institute, Tamagawa University School of Medicine, 6-1-1 Tamagawagakuen, Machida, Tokyo 194-8610, Japan.
| | - Yasuhiro Fukushima
- Brain Science Institute, Tamagawa University School of Medicine, 6-1-1 Tamagawagakuen, Machida, Tokyo 194-8610, Japan; Kawasaki University of Medical Welfare, 288 Matsushima, Kurashiki, Okayama 701-0193, Japan.
| | - Satoshi Fujii
- Department of Physiology, Yamagata University of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
| | - Yoshihiko Yamazaki
- Department of Physiology, Yamagata University of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
| | - Takeshi Aihara
- College of Engineering, Tamagawa University, 6-1-1 Tamagawagakuen, Machida, Tokyo 194-8610, Japan; Brain Science Institute, Tamagawa University School of Medicine, 6-1-1 Tamagawagakuen, Machida, Tokyo 194-8610, Japan.
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27
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Abongwa M, Buxton SK, Courtot E, Charvet CL, Neveu C, McCoy CJ, Verma S, Robertson AP, Martin RJ. Pharmacological profile of Ascaris suum ACR-16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues. Br J Pharmacol 2016; 173:2463-77. [PMID: 27238203 PMCID: PMC4959957 DOI: 10.1111/bph.13524] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 04/25/2016] [Accepted: 05/17/2016] [Indexed: 12/31/2022] Open
Abstract
Background and Purpose Control of nematode parasite infections relies largely on anthelmintic drugs, several of which act on nicotinic ACh receptors (nAChRs), and there are concerns about the development of resistance. There is an urgent need for development of new compounds to overcome resistance and novel anthelmintic drug targets. We describe the functional expression and pharmacological characterization of a homomeric nAChR, ACR‐16, from a nematode parasite. Experimental Approach Using RT‐PCR, molecular cloning and two‐electrode voltage clamp electrophysiology, we localized acr‐16 mRNA in Ascaris suum (Asu) and then cloned and expressed acr‐16 cRNA in Xenopus oocytes. Sensitivity of these receptors to cholinergic anthelmintics and a range of nicotinic agonists was tested. Key Results Amino acid sequence comparison with vertebrate nAChR subunits revealed ACR‐16 to be most closely related to α7 receptors, but with some striking distinctions. acr‐16 mRNA was recovered from Asu somatic muscle, pharynx, ovijector, head and intestine. In electrophysiological experiments, the existing cholinergic anthelmintic agonists (morantel, levamisole, methyridine, thenium, bephenium, tribendimidine and pyrantel) did not activate Asu‐ACR‐16 (except for a small response to oxantel). Other nAChR agonists: nicotine, ACh, cytisine, 3‐bromocytisine and epibatidine, produced robust current responses which desensitized at a rate varying with the agonists. Unlike α7, Asu‐ACR‐16 was insensitive to α‐bungarotoxin and did not respond to genistein or other α7 positive allosteric modulators. Asu‐ACR‐16 had lower calcium permeability than α7 receptors. Conclusions and Implications We suggest that ACR‐16 has diverse tissue‐dependent functions in nematode parasites and is a suitable drug target for development of novel anthelmintic compounds.
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Affiliation(s)
- Melanie Abongwa
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Samuel K Buxton
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Elise Courtot
- INRA, UMR Infectiologie et Santé Publique, Nouzilly, France.,Université François Rabelais de Tours, UMR Infectiologie et Santé Publique, Tours, France
| | - Claude L Charvet
- INRA, UMR Infectiologie et Santé Publique, Nouzilly, France.,Université François Rabelais de Tours, UMR Infectiologie et Santé Publique, Tours, France
| | - Cédric Neveu
- INRA, UMR Infectiologie et Santé Publique, Nouzilly, France.,Université François Rabelais de Tours, UMR Infectiologie et Santé Publique, Tours, France
| | - Ciaran J McCoy
- School of Biological Sciences, Medical Biology Centre, Queen's University Belfast, Belfast, UK
| | - Saurabh Verma
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Alan P Robertson
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Richard J Martin
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
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28
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Ni KM, Hou XJ, Yang CH, Dong P, Li Y, Zhang Y, Jiang P, Berg DK, Duan S, Li XM. Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep. eLife 2016; 5. [PMID: 26880556 PMCID: PMC4764559 DOI: 10.7554/elife.10382] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/23/2015] [Indexed: 12/15/2022] Open
Abstract
Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep. DOI:http://dx.doi.org/10.7554/eLife.10382.001 Sleep is one of the most familiar activities in our lives and yet there are still many unanswered questions related to how it is regulated. The cholinergic system (or the part of the nervous system that sends signals using a chemical called acetylcholine) is thought to be important for the phase of sleep that is most similar to being awake, so-called REM sleep. This collection of nerve cells has also been implicated in the process of waking up from sleep. However, it remains unclear how the cholinergic system acts on sleep. Ni, Hou et al. have now used a technique called optogenetics to use light to stimulate the cholinergic system in specific areas in the brains of mice. These experiments found that the activation of the cholinergic system caused awake mice to fall asleep, and promoted more non-REM sleep in sleeping mice. As such, this discovery challenges the previously held view that cholinergic activity was linked to waking up. Acetylcholine affects cells in a similar way to nicotine from cigarettes. In the future, Ni, Hou et al. would like to explore how many nicotine-like substances are released by the cholinergic system in specific brain areas, and to further investigate when and how sleep is promoted. DOI:http://dx.doi.org/10.7554/eLife.10382.002
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Affiliation(s)
- Kun-Ming Ni
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao-Jun Hou
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China.,Fuzhou Children's Hospital, Fujian, China
| | - Ci-Hang Yang
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Ping Dong
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Li
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Zhang
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Ping Jiang
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Darwin K Berg
- Neurobiology Section, Division of Biological Sciences, Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, United States
| | - Shumin Duan
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao-Ming Li
- Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, China.,Soft Matter Research Center, Zhejiang University, Hangzhou, China
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John D, Berg DK. Long-lasting changes in neural networks to compensate for altered nicotinic input. Biochem Pharmacol 2015; 97:418-424. [PMID: 26206188 PMCID: PMC4600434 DOI: 10.1016/j.bcp.2015.07.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 07/07/2015] [Indexed: 11/21/2022]
Abstract
The nervous system must balance excitatory and inhibitory input to constrain network activity levels within a proper dynamic range. This is a demanding requirement during development, when networks form and throughout adulthood as networks respond to constantly changing environments. Defects in the ability to sustain a proper balance of excitatory and inhibitory activity are characteristic of numerous neurological disorders such as schizophrenia, Alzheimer's disease, and autism. A variety of homeostatic mechanisms appear to be critical for balancing excitatory and inhibitory activity in a network. These are operative at the level of individual neurons, regulating their excitability by adjusting the numbers and types of ion channels, and at the level of synaptic connections, determining the relative numbers of excitatory versus inhibitory connections a neuron receives. Nicotinic cholinergic signaling is well positioned to contribute at both levels because it appears early in development, extends across much of the nervous system, and modulates transmission at many kinds of synapses. Further, it is known to influence the ratio of excitatory-to-inhibitory synapses formed on neurons during development. GABAergic inhibitory neurons are likely to be key for maintaining network homeostasis (limiting excitatory output), and nicotinic signaling is known to prominently regulate the activity of several GABAergic neuronal subtypes. But how nicotinic signaling achieves this and how networks may compensate for the loss of such input are important questions remaining unanswered. These issues are reviewed.
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Affiliation(s)
- Danielle John
- Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093-0357, United States; Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093-0357, United States
| | - Darwin K Berg
- Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093-0357, United States; Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093-0357, United States.
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Bertrand D, Lee CHL, Flood D, Marger F, Donnelly-Roberts D. Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors. Pharmacol Rev 2015; 67:1025-73. [PMID: 26419447 DOI: 10.1124/pr.113.008581] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of α7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of α7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of α7 nAChRs in cognition, the translation of small molecules affecting α7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of α7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of α7 nAChRs and their relevance as a target in specific functional systems and disease states.
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Affiliation(s)
- Daniel Bertrand
- HiQScreen Sàrl, Geneva, Switzerland (D.B., F.M.); AbbVie Inc., North Chicago, Illinois (C-H.L.L., D.D-R.); and FORUM Pharmaceuticals Inc., Waltham, Massachusetts (D.F.)
| | - Chih-Hung L Lee
- HiQScreen Sàrl, Geneva, Switzerland (D.B., F.M.); AbbVie Inc., North Chicago, Illinois (C-H.L.L., D.D-R.); and FORUM Pharmaceuticals Inc., Waltham, Massachusetts (D.F.)
| | - Dorothy Flood
- HiQScreen Sàrl, Geneva, Switzerland (D.B., F.M.); AbbVie Inc., North Chicago, Illinois (C-H.L.L., D.D-R.); and FORUM Pharmaceuticals Inc., Waltham, Massachusetts (D.F.)
| | - Fabrice Marger
- HiQScreen Sàrl, Geneva, Switzerland (D.B., F.M.); AbbVie Inc., North Chicago, Illinois (C-H.L.L., D.D-R.); and FORUM Pharmaceuticals Inc., Waltham, Massachusetts (D.F.)
| | - Diana Donnelly-Roberts
- HiQScreen Sàrl, Geneva, Switzerland (D.B., F.M.); AbbVie Inc., North Chicago, Illinois (C-H.L.L., D.D-R.); and FORUM Pharmaceuticals Inc., Waltham, Massachusetts (D.F.)
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31
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Wallace TL, Bertrand D. Neuronal α7 Nicotinic Receptors as a Target for the Treatment of Schizophrenia. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2015; 124:79-111. [PMID: 26472526 DOI: 10.1016/bs.irn.2015.08.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Schizophrenia is a lifelong disease, the burden of which is often underestimated. Characterized by positive (e.g., hallucinations) and negative (e.g., avolition, amotivation) symptoms, schizophrenia is also accompanied with profound impairments in cognitive function that progress throughout the development of the disease. Although treatment with antipsychotic medications can effectively dampen some of the positive symptoms, these medications largely fail to reverse cognitive deficits or to mitigate negative symptoms. With a worldwide prevalence of approximately 1%, schizophrenia remains a large unmet medical need that stands to benefit greatly from (1) continued research to better understand the biological underpinnings of the disease and (2) the targeted development of novel therapeutics to improve the lives of those affected individuals. Improvements in our understanding of the neuronal networks associated with schizophrenia as well as progress in identifying genetic risk factors and environmental conditions that may predispose individuals to developing the disease are advancing new strategies to study and treat it. Herein, we review the evidence that supports the role of α7 nicotinic acetylcholine receptors in the central nervous system and why these receptors constitute a promising target to treat some of the prominent symptoms of schizophrenia.
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Duan JJ, Lozada AF, Gou CY, Xu J, Chen Y, Berg DK. Nicotine recruits glutamate receptors to postsynaptic sites. Mol Cell Neurosci 2015; 68:340-9. [PMID: 26365992 DOI: 10.1016/j.mcn.2015.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 08/04/2015] [Accepted: 09/07/2015] [Indexed: 01/20/2023] Open
Abstract
Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input that the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors.
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Affiliation(s)
- Jing-Jing Duan
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Neurobiology Section, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0357, United States
| | - Adrian F Lozada
- Neurobiology Section, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0357, United States
| | - Chen-Yu Gou
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jing Xu
- Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yuan Chen
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
| | - Darwin K Berg
- Neurobiology Section, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0357, United States.
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Dani JA. Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2015; 124:3-19. [PMID: 26472524 DOI: 10.1016/bs.irn.2015.07.001] [Citation(s) in RCA: 190] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Nicotinic acetylcholine receptors (nAChRs) belong to the "Cys-loop" superfamily of ligand-gated ion channels that includes GABAA, glycine, and serotonin (5-HT3) receptors. There are 16 homologous mammalian nAChR subunits encoded by a multigene family. These subunits combine to form many different nAChR subtypes with various expression patterns, diverse functional properties, and differing pharmacological characteristics. Because cholinergic innervation is pervasive and nAChR expression is extremely broad, practically every area of the brain is impinged upon by nicotinic mechanisms. This review briefly examines the structural and functional properties of the receptor/channel complex itself. The review also summarizes activation and desensitization of nAChRs by the low nicotine concentrations obtained from tobacco. Knowledge of the three-dimensional structure and the structural characteristics of channel gating has reached an advanced stage. Likewise, the basic functional properties of the channel also are reasonably well understood. It is these receptor/channel properties that underlie the participation of nAChRs in nearly every anatomical region of the mammalian brain.
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Affiliation(s)
- John A Dani
- Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Cheng Q, Yakel JL. The effect of α7 nicotinic receptor activation on glutamatergic transmission in the hippocampus. Biochem Pharmacol 2015. [PMID: 26212541 DOI: 10.1016/j.bcp.2015.07.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory, however the cellular mechanism of these actions remains elusive. With help from newly developed biosensors and optogenetic tools, recent studies provide new insights on signaling mechanisms involved in the activation of nAChRs. Here we will review α7 nAChR's action in the tri-synaptic pathway in the hippocampus. The effects of α7 nAChR activation via either exogenous compounds or endogenous cholinergic innervation are detailed for spontaneous and evoked glutamatergic synaptic transmission and synaptic plasticity, as well as the underlying signaling mechanisms. In summary, α7 nAChRs trigger intracellular calcium rise and calcium-dependent signaling pathways to enhance glutamate release and induce glutamatergic synaptic plasticity.
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Affiliation(s)
- Qing Cheng
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA
| | - Jerrel L Yakel
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA
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Hay YA, Lambolez B, Tricoire L. Nicotinic Transmission onto Layer 6 Cortical Neurons Relies on Synaptic Activation of Non-α7 Receptors. Cereb Cortex 2015; 26:2549-2562. [PMID: 25934969 DOI: 10.1093/cercor/bhv085] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nicotinic excitation in neocortex is mediated by low-affinity α7 receptors and by high-affinity α4β2 receptors. There is evidence that α7 receptors are synaptic, but it is unclear whether high-affinity receptors are activated by volume transmission or synaptic transmission. To address this issue, we characterized responses of excitatory layer 6 (L6) neurons to optogenetic release of acetylcholine (ACh) in cortical slices. L6 responses consisted in a slowly decaying α4β2 current and were devoid of α7 component. Evidence that these responses were mediated by synapses was 4-fold. 1) Channelrhodopsin-positive cholinergic varicosities made close appositions onto responsive neurons. 2) Inhibition of ACh degradation failed to alter onset kinetics and amplitude of currents. 3) Quasi-saturation of α4β2 receptors occurred upon ACh release. 4) Response kinetics were unchanged in low release probability conditions. Train stimulations increased amplitude and decay time of responses and these effects appeared to involve recruitment of extrasynaptic receptors. Finally, we found that the α5 subunit, known to be associated with α4β2 in L6, regulates short-term plasticity at L6 synapses. Our results are consistent with previous anatomical observations of widespread cholinergic synapses and suggest that a significant proportion of these small synapses operate via high-affinity nicotinic receptors.
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Affiliation(s)
- Y Audrey Hay
- Sorbonne Universités, UPMC Univ Paris 06, UM119, Neuroscience Paris Seine, Paris F-75005, France.,Centre National de la Recherche Scientifique (CNRS), UMR 8246, Paris F-75005, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), U1130, Paris F-75005, France
| | - Bertrand Lambolez
- Sorbonne Universités, UPMC Univ Paris 06, UM119, Neuroscience Paris Seine, Paris F-75005, France.,Centre National de la Recherche Scientifique (CNRS), UMR 8246, Paris F-75005, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), U1130, Paris F-75005, France
| | - Ludovic Tricoire
- Sorbonne Universités, UPMC Univ Paris 06, UM119, Neuroscience Paris Seine, Paris F-75005, France.,Centre National de la Recherche Scientifique (CNRS), UMR 8246, Paris F-75005, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), U1130, Paris F-75005, France
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36
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The nicotinic receptor Alpha7 impacts the mouse lung response to LPS through multiple mechanisms. PLoS One 2015; 10:e0121128. [PMID: 25803612 PMCID: PMC4372581 DOI: 10.1371/journal.pone.0121128] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 01/28/2015] [Indexed: 01/09/2023] Open
Abstract
The nicotinic acetylcholine receptor alpha7 (α7) is expressed by neuronal and non-neuronal cells throughout the body. We examined the mechanisms of the lung inflammatory response to intranasal (i.n.) lipopolysaccharide (LPS) regulated by α7. This was done in mice using homologous recombination to introduce a point mutation in the α7 receptor that replaces the glutamate residue 260 that lines the pore with alanine (α7E260A), which has been implicated in controlling the exceptional calcium ion conductance of this receptor. The α7E260A mice exhibit normal inflammatory cell recruitment to the blood in response to i.n. LPS administration. This differs from the α7knock-out (α7KO) in which upstream signaling to initiate the recruitment to the blood following i.n. LPS is significantly impaired. While hematopoietic cells are recruited to the bloodstream in the α7E260A mouse, they fail to be recruited efficiently into both the interstitium and alveolar spaces of the lung. Bone marrow reconstitution experiments demonstrate that the responsiveness of both CD45+ and CD45- cells of the α7E260A mouse are impaired. The expression of several pro-inflammatory cytokine and chemokine RNAs including TNFα, IL-1α, Ccl2 and Cxcl10 are decreased in the α7E260A mouse. However, there is a substantial increase in IL-13 expression by CD45- lung interstitial cells in the α7E260A mouse. Our results support the conclusion that α7 functional pleiotropy contributes to modulating the tissue response to an inflammatory insult through impacting upon a variety of mechanisms reflecting the individual cell composition of the lung.
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Lipovsek M, Fierro A, Pérez EG, Boffi JC, Millar NS, Fuchs PA, Katz E, Elgoyhen AB. Tracking the molecular evolution of calcium permeability in a nicotinic acetylcholine receptor. Mol Biol Evol 2014; 31:3250-65. [PMID: 25193338 PMCID: PMC4245820 DOI: 10.1093/molbev/msu258] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Nicotinic acetylcholine receptors are a family of ligand-gated nonselective cationic channels that participate in fundamental physiological processes at both the central and the peripheral nervous system. The extent of calcium entry through ligand-gated ion channels defines their distinct functions. The α9α10 nicotinic cholinergic receptor, expressed in cochlear hair cells, is a peculiar member of the family as it shows differences in the extent of calcium permeability across species. In particular, mammalian α9α10 receptors are among the ligand-gated ion channels which exhibit the highest calcium selectivity. This acquired differential property provides the unique opportunity of studying how protein function was shaped along evolutionary history, by tracking its evolutionary record and experimentally defining the amino acid changes involved. We have applied a molecular evolution approach of ancestral sequence reconstruction, together with molecular dynamics simulations and an evolutionary-based mutagenesis strategy, in order to trace the molecular events that yielded a high calcium permeable nicotinic α9α10 mammalian receptor. Only three specific amino acid substitutions in the α9 subunit were directly involved. These are located at the extracellular vestibule and at the exit of the channel pore and not at the transmembrane region 2 of the protein as previously thought. Moreover, we show that these three critical substitutions only increase calcium permeability in the context of the mammalian but not the avian receptor, stressing the relevance of overall protein structure on defining functional properties. These results highlight the importance of tracking evolutionarily acquired changes in protein sequence underlying fundamental functional properties of ligand-gated ion channels.
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Affiliation(s)
- Marcela Lipovsek
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Angélica Fierro
- Department of Organic Chemistry, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Edwin G Pérez
- Department of Organic Chemistry, Faculty of Chemistry, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan C Boffi
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Neil S Millar
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
| | - Paul A Fuchs
- Department of Otolaryngology, Head and Neck Surgery, and Center for Hearing and Balance, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Eleonora Katz
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ana Belén Elgoyhen
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Dr. Héctor N Torres, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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38
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Ju Y, Asahi T, Sawamura N. Arctic mutant Aβ40 aggregates on α7 nicotinic acetylcholine receptors and inhibits their functions. J Neurochem 2014; 131:667-74. [DOI: 10.1111/jnc.12837] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 07/18/2014] [Accepted: 07/18/2014] [Indexed: 11/28/2022]
Affiliation(s)
- Ye Ju
- Faculty of Science and Engineering; Waseda University; Shinjuku Tokyo Japan
| | - Toru Asahi
- Faculty of Science and Engineering; Waseda University; Shinjuku Tokyo Japan
- Consolidated Research Institute for Advanced Science and Medical Care (ASMeW); Waseda University; Shinjuku Tokyo Japan
| | - Naoya Sawamura
- Faculty of Science and Engineering; Waseda University; Shinjuku Tokyo Japan
- Consolidated Research Institute for Advanced Science and Medical Care (ASMeW); Waseda University; Shinjuku Tokyo Japan
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39
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Melis M, Pistis M. Targeting the interaction between fatty acid ethanolamides and nicotinic receptors: Therapeutic perspectives. Pharmacol Res 2014; 86:42-9. [DOI: 10.1016/j.phrs.2014.03.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 03/06/2014] [Accepted: 03/24/2014] [Indexed: 12/22/2022]
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Abstract
Elucidating the roles of neuronal cell types for physiology and behavior is essential for understanding brain functions. Perturbation of neuron electrical activity can be used to probe the causal relationship between neuronal cell types and behavior. New genetically encoded neuron perturbation tools have been developed for remotely controlling neuron function using small molecules that activate engineered receptors that can be targeted to cell types using genetic methods. Here we describe recent progress for approaches using genetically engineered receptors that selectively interact with small molecules. Called "chemogenetics," receptors with diverse cellular functions have been developed that facilitate the selective pharmacological control over a diverse range of cell-signaling processes, including electrical activity, for molecularly defined cell types. These tools have revealed remarkably specific behavioral physiological influences for molecularly defined cell types that are often intermingled with populations having different or even opposite functions.
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Affiliation(s)
- Scott M Sternson
- Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147;
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41
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Yakel JL. Nicotinic ACh receptors in the hippocampal circuit; functional expression and role in synaptic plasticity. J Physiol 2014; 592:4147-53. [PMID: 24860170 DOI: 10.1113/jphysiol.2014.273896] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Acetylcholine (ACh) can regulate neuronal excitability in the hippocampus, an important area in the brain for learning and memory, by acting on both nicotinic (nAChRs) and muscarinic ACh receptors. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca (MS-DBB), and we investigated how their activation regulated hippocampal synaptic plasticity. We found that activation of these endogenous cholinergic inputs can directly induce different forms of hippocampal synaptic plasticity with a timing precision in the millisecond range. Furthermore, we observed a prolonged enhancement of excitability both pre- and postsynaptically. Lastly we found that the presence of the α7 nAChR subtype to both pre- and postsynaptic sites appeared to be required to induce this plasticity. We propose that α7 nAChRs coordinate pre- and postsynaptic activities to induce glutamatergic synaptic plasticity, and thus provide a novel mechanism underlying physiological neuronal communication that could lead to timing-dependent synaptic plasticity in the hippocampus.
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Affiliation(s)
- Jerrel L Yakel
- Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA
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42
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Abstract
Selective strengthening of specific glutamatergic synapses in the mammalian hippocampus is critical for encoding new memories. This is most commonly achieved by input-specific Hebbian-type plasticity involving glutamate-dependent coincident presynaptic and postsynaptic depolarization. Our results demonstrate a novel mechanism by which nicotinic signaling, independently of coincident fast glutamatergic transmission, increases synaptic strength in the hippocampus. Electrophysiological recordings from rat hippocampal neurons in culture revealed that 1-3 h of exposure to 1 μm nicotine, even with action potentials being blocked, produced increases in both the frequency and amplitude of miniature EPSCs. Possible mechanisms were analyzed both in mouse organotypic slice culture and in rat cell culture by inducing the cells to express super-ecliptic pHluorin-tagged GluA1-containing AMPA receptors, which fluoresce only on the cell surface. Pharmacological and genetic manipulation of the cells, in combination with fluorescence-recovery-after-photobleaching experiments, revealed that nicotine, acting through α7-containing nicotinic acetylcholine receptors on the postsynaptic neuron, induces the stabilization and accumulation of GluA1-containing AMPA receptors on dendritic spines. The process relies on intracellular calcium signaling, PDZ [postsynaptic density-95 (PSD-95)/Discs large (Dlg)/zona occludens-1 (ZO-1)] interactions with members of the PSD-95 family, and lateral diffusion of the GluA1 receptors on the cell surface. These findings define a new avenue by which nicotinic signaling modulates synaptic mechanisms thought to subserve learning and memory.
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Presynaptic α7 nicotinic acetylcholine receptors enhance hippocampal mossy fiber glutamatergic transmission via PKA activation. J Neurosci 2014; 34:124-33. [PMID: 24381273 DOI: 10.1523/jneurosci.2973-13.2014] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory. However, the mechanism of nicotine's action on cognitive function remains elusive. We performed patch-clamp recordings from hippocampal CA3 pyramidal neurons to determine the effect of nicotine on mossy fiber glutamatergic synaptic transmission. We found that nicotine in combination with NS1738, an α7 nAChR-positive allosteric modulator, strongly potentiated the amplitude of evoked EPSCs (eEPSCs), and reduced the EPSC paired-pulse ratio. The action of nicotine and NS1738 was mimicked by PNU-282987 (an α7 nAChR agonist), and was absent in α7 nAChR knock-out mice. These data indicate that activation of α7 nAChRs was both necessary and sufficient to enhance the amplitude of eEPSCs. BAPTA applied postsynaptically failed to block the action of nicotine and NS1738, suggesting again a presynaptic action of the α7 nAChRs. We also observed α7 nAChR-mediated calcium rises at mossy fiber giant terminals, indicating the presence of functional α7 nAChRs at presynaptic terminals. Furthermore, the addition of PNU-282987 enhanced action potential-dependent calcium transient at these terminals. Last, the potentiating effect of PNU-282987 on eEPSCs was abolished by inhibition of protein kinase A (PKA). Our findings indicate that activation of α7 nAChRs at presynaptic sites, via a mechanism involving PKA, plays a critical role in enhancing synaptic efficiency of hippocampal mossy fiber transmission.
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Lateral mobility of presynaptic α7-containing nicotinic receptors and its relevance for glutamate release. J Neurosci 2013; 33:17062-71. [PMID: 24155310 DOI: 10.1523/jneurosci.1482-13.2013] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Surface diffusion of postsynaptic receptors shapes synaptic transmission. Presynaptic receptors also influence transmission, but the relevance of their mobility for synaptic function is unknown. Using single-particle tracking with quantum dots, we show that calcium-permeable α7-containing nicotinic acetylcholine receptors (α7-nAChRs), capable of promoting transmitter release, are mobile on presynaptic terminals but constrained in synaptic space on rat hippocampal neurons in culture. Additional immobilization of presynaptic α7-nAChRs by antibody crosslinking increases glutamate release capacity as seen in the frequency of spontaneous miniature postsynaptic currents and the size of the readily releasable pool of transmitter. Conversely, blocking glutamate release by targeting tetanus toxin to individual synapses increases α7-nAChR dwell time at presynaptic sites. The effects on release require functional α7-nAChRs and may to depend on CAST/ELKS (calpastatin/glutamine, leucine, lysine, and serine-rich protein), which an unbiased proteomic screen yielded. The results support a new homeostatic regulatory mechanism in which α7-nAChR restrain may be adjusted as needed at presynaptic sites via active zone proteins to maintain transmitter release capability.
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45
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Colón-Sáez JO, Yakel JL. A mutation in the extracellular domain of the α7 nAChR reduces calcium permeability. Pflugers Arch 2013; 466:1571-9. [PMID: 24177919 DOI: 10.1007/s00424-013-1385-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 10/11/2013] [Accepted: 10/12/2013] [Indexed: 10/26/2022]
Abstract
The α7 neuronal nicotinic acetylcholine receptor (nAChR) displays the highest calcium permeability among the different subtypes of nAChRs expressed in the mammalian brain and can impact cellular events including neurotransmitter release, second messenger cascades, cell survival, and apoptosis. The selectivity for cations in nAChRs is thought to be achieved in part by anionic residues which are located on either side of the channel mouth and increase relative cationic concentration. Mutagenesis studies have improved our understanding of the role of the second transmembrane domain and the intracellular loop of the channel in ion selectivity. However, little is known about the influence that the extracellular domain (ECD) plays in ion permeation. In the α7 nAChR, it has been found that the ECD contains a ring of ten aspartates (two per subunit) that is believed to face the lumen of the pore and could attract cations for permeation. Using mutagenesis and a combination of electrophysiology and imaging techniques, we tested the possible involvement of these aspartate residues in the calcium permeability of the rat α7 nAChR. We found that one of these residues (the aspartate at position 44) appears to be essential since mutating it to alanine resulted in a decrease in amplitude for both whole cell and single-channel responses and in the complete disappearance of detectable calcium changes in most cells, which indicates that the ECD of the α7 nAChR plays a key role in calcium permeation.
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Affiliation(s)
- José O Colón-Sáez
- Laboratory of Neurobiology, National Institute of Environmental Health Science, National Institutes of Health, Department of Health and Human Services, PO Box 12233, Research Triangle Park, NC, 27709, USA
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46
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Wang X, Lippi G, Carlson DM, Berg DK. Activation of α7-containing nicotinic receptors on astrocytes triggers AMPA receptor recruitment to glutamatergic synapses. J Neurochem 2013; 127:632-43. [PMID: 24032433 DOI: 10.1111/jnc.12436] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 07/31/2013] [Accepted: 08/26/2013] [Indexed: 02/02/2023]
Abstract
Astrocytes, an abundant form of glia, are known to promote and modulate synaptic signaling between neurons. They also express α7-containing nicotinic acetylcholine receptors (α7-nAChRs), but the functional relevance of these receptors is unknown. We show here that stimulation of α7-nAChRs on astrocytes releases components that induce hippocampal neurons to acquire more α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors post-synaptically at glutamatergic synapses. The increase is specific in that no change is seen in synaptic NMDA receptor clusters or other markers for glutamatergic synapses, or in markers for GABAergic synapses. Moreover, the increases in AMPA receptors on the neuron surface are accompanied by increases in the frequency of spontaneous miniature synaptic currents mediated by the receptors and increases in the ratio of evoked synaptic currents mediated by AMPA versus NMDA receptors. This suggests that stimulating α7-nAChRs on astrocytes can convert 'silent' glutamatergic synapses to functional status. Astrocyte-derived thrombospondin is necessary but not sufficient for the effect, while tumor necrosis factor-α is sufficient but not necessary. The results identify astrocyte α7-nAChRs as a novel pathway through which nicotinic cholinergic signaling can promote the development of glutamatergic networks, recruiting AMPA receptors to post-synaptic sites and rendering the synapses more functional. We find that activation of nicotinic receptors on astrocytes releases a component that specifically recruits AMPA receptors to glutamatergic synapses. The recruitment appears to occur preferentially at what may be 'silent synapses', that is, synapses that have all the components required for glutamatergic transmission (including NMDA receptors) but lack sufficient AMPA receptors to generate a response. The results are unexpected and open up new possibilities for mechanisms underlying network formation and synaptic plasticity.
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Affiliation(s)
- Xulong Wang
- Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA
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47
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Molgó J, Aráoz R, Benoit E, Iorga BI. Physical and virtual screening methods for marine toxins and drug discovery targeting nicotinic acetylcholine receptors. Expert Opin Drug Discov 2013; 8:1203-23. [DOI: 10.1517/17460441.2013.822365] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Alzoubi KH, Srivareerat M, Tran TT, Alkadhi KA. Role of α7- and α4β2-nAChRs in the neuroprotective effect of nicotine in stress-induced impairment of hippocampus-dependent memory. Int J Neuropsychopharmacol 2013; 16:1105-1113. [PMID: 23067572 DOI: 10.1017/s1461145712001046] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
We have previously shown that nicotine prevents stress-induced memory impairment. In this study, we have investigated the role of α7- and α4β2-nicotinic acetylcholine receptors (nAChRs) in the protective effect of nicotine during chronic stress conditions. Chronic psychosocial stress was induced using a form of rat intruder model. During stress, specific antagonist for either α7-nAChRs [methyllycaconitine (MLA)] or α4β2-nAChRs [dihydro-β-erythroidine (DHβE)] was infused into the hippocampus using a 4-wk osmotic pump at a rate of 82 μg/side.d and 41 μg/side.d, respectively. Three weeks after the start of infusion, all rats were subjected to a series of cognitive tests in the radial arm water maze (RAWM) for six consecutive days or until the animal reached days to criterion (DTC) in the fourth acquisition trial and in all memory tests. DTC is defined as the number of days the animal takes to make no more than one error in three consecutive days. In the short-term memory test, MLA-infused stressed/nicotine-treated rats made similar errors to those of stress and significantly more errors compared to those of stress/nicotine, nicotine or control groups. This finding was supported by the DTC values for the short memory tests. Thus, MLA treatment blocked the neuroprotective effect of nicotine during chronic stress. In contrast, DHβE infusion did not affect the RAWM performance of stress/nicotine animals. These results strongly suggest the involvement of α7-nAChRs, but not α4β2-nAChRs, in the neuroprotective effect of chronic nicotine treatment during chronic stress conditions.
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Affiliation(s)
- Karem H Alzoubi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
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49
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Melis M, Scheggi S, Carta G, Madeddu C, Lecca S, Luchicchi A, Cadeddu F, Frau R, Fattore L, Fadda P, Ennas MG, Castelli MP, Fratta W, Schilstrom B, Banni S, De Montis MG, Pistis M. PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors. J Neurosci 2013; 33:6203-11. [PMID: 23554501 PMCID: PMC6618938 DOI: 10.1523/jneurosci.4647-12.2013] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 02/15/2013] [Accepted: 02/21/2013] [Indexed: 11/21/2022] Open
Abstract
Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the β2 subunit (β2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate β2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the β2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of β2*-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.
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Affiliation(s)
- Miriam Melis
- Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy.
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Yakel JL. Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease. Pflugers Arch 2013; 465:441-50. [PMID: 23307081 PMCID: PMC3633680 DOI: 10.1007/s00424-012-1200-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 12/03/2012] [Accepted: 12/03/2012] [Indexed: 12/13/2022]
Abstract
The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability throughout the nervous system by acting on both the cys-loop ligand-gated nicotinic ACh receptor channels (nAChRs) and the G protein-coupled muscarinic ACh receptors (mAChRs). The hippocampus is an important area in the brain for learning and memory, where both nAChRs and mAChRs are expressed. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca, the activation of which can activate both nAChRs and mAChRs in the hippocampus and regulate synaptic communication and induce oscillations that are thought to be important for cognitive function. Dysfunction in the hippocampal cholinergic system has been linked with cognitive deficits and a variety of neurological disorders and diseases, including Alzheimer's disease and schizophrenia. My lab has focused on the role of the nAChRs in regulating hippocampal function, from understanding the expression and functional properties of the various subtypes of nAChRs, and what role these receptors may be playing in regulating synaptic plasticity. Here, I will briefly review this work, and where we are going in our attempts to further understand the role of these receptors in learning and memory, as well as in disease and neuroprotection.
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Affiliation(s)
- Jerrel L Yakel
- Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop F2-08, Research Triangle Park, NC 27709, USA.
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