Intracellular calcium channels: Potential targets for type 2 diabetes mellitus?

Abstract

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder. Despite the availability of numerous pharmacotherapies, a range of adverse reactions, including hypoglycemia, gastrointestinal discomfort, and lactic acidosis, limits their patient applicability and long-term application. Therefore, it is necessary to screen novel therapeutic drugs for T2DM treatment that have high efficacy but few adverse effects. AMP-activated protein kinase (AMPK) stands out as one of the most powerful targets for T2DM treatment. It can be activated through energy-sensing or calcium signaling. Medications that activate AMPK through the energy-sensing mechanism exhibit remarkable potency, but they are accompanied by lactic acidosis, carrying an alarmingly high mortality rate. Interestingly, medications that activate AMPK through calcium signaling, such as gliclazide, seldom induce lactic acidosis. However, the efficacy of gliclazide is much lower than metformin. Therefore, it is necessary to explore targets that activate AMPK via calcium signaling to avoid lactic acidosis while maintaining high potency. Ion channels are the main controller of intracellular calcium flow. Specific agonists and inhibitors targeting ion channels have been reported to activate AMPK. In this review, we will summarize the structure and function of calcium-permeable ion channels and discuss the potential of targeting these calcium channels for T2DM treatment.

Key Words: Ion channels; AMP-activated protein kinase; Calcium; Diabetes; Lactic acidosis

Core Tip: The applicability and long-term use of drugs for type 2 diabetes mellitus (T2DM) treatment is limited due to their adverse effects. Drugs that activate AMP-activated protein kinase (AMPK) via calcium signaling exhibit fewer adverse effects such as lactic acidosis. However, the potency of these drugs is limited. Therefore, it is necessary to screen novel drugs with high efficacy but few adverse effects. The calcium channels control intracellular calcium flux, which could be potential targets for T2DM treatment via AMPK. This review summarizes 15 calcium channels, and discuss the potential of targeting these calcium channels for T2DM treatment.

INTRODUCTION

Diabetes mellitus is a group of metabolic conditions characterized by hyperglycemia. It is the most common metabolic condition in the world, and its incidence is increasing. There are several types of diabetes. Type 2 diabetes mellitus (T2DM) is the most common type[1], and it is characterized by insulin resistance[2]. Individuals with T2DM exhibit symptoms including polydipsia, polyphagia, polyuria, weight loss, xerostomia, and fatigue. In severe cases, it leads to diabetic foot, diabetic retinopathy, heart failure, diabetic peripheral neuropathy, and even amputation and death[3-6]. Under normal conditions, insulin regulates the cellular trafficking of glucose transporter isoform 4 (GLUT4) protein to the plasma membrane (PM), facilitating the transport of glucose from the blood into cells, thereby maintaining glucose homeostasis[7]. In the case of chronic excessive nutrition, the pancreas will constantly secrete elevated amounts of insulin, causing dysfunction of islet β cells and ultimately insulin resistance[8], alongside GLUT4 retention in storage vesicles, leading to high blood glucose levels[9].

The pharmacological treatment of T2DM mainly encompasses oral medication and insulin injection. Due to the limited acceptance of insulin injection, oral medication remains the primary treatment for the majority of patients[10]. Oral medications for T2DM treatment that are commercially available can be categorized into insulin secretagogues and non-insulin antidiabetic agents (Table 1). Targets for insulin secretagogues primarily encompass the glucagon-like peptide-1 (GLP-1) receptor, dipeptidyl peptidase-4 (DPP-4), and the ATP-sensitive potassium channels (K_ATP channels)[11]. Both GLP-1 receptor agonists (exenatide) or DPP-4 inhibitors (sitagliptin) can enhance the activity of GLP-1, which promotes glucose-dependent insulin secretion, facilitating glucose uptake. Inhibitors of the K_ATP channel (glibenclamide) modulate K⁺/Ca²⁺ homeostasis, leading to an enhanced influx of calcium, which subsequently facilitates insulin secretion. Long-term utilization of insulin secretagogues, including sitagliptin and glibenclamide, has been associated with various adverse reactions such as hypoglycemia, hyperinsulinemia, obesity, gastrointestinal discomfort, renal impairment, and allergic responses[12,13].

Table 1 Current commercial medications for type 2 diabetes mellitus treatment.

Classification	Medication	Target	Adverse reaction	Limitation
Insulin secretagogue	Glibenclamide	ATP-sensitive potassium channel	Hypoglycemia; weight gain; gastrointestinal disorders	Contraindicated in patients with sulfonamide allergies
	Tirzepatide	Glucagon-like peptide-1 receptor	Risk of thyroid myeloid tumors	Contraindicated in patients with medullary thyroid carcinoma or multiple endocrine neoplastic syndrome type 2
	Semaglutide		Risk of thyroid myeloid tumors
	Exenatide		Risk of pancreatitis
	Sitagliptin	Dipeptidyl peptidase-4	Risk of pancreatitis; metabolic and nutritional disorders	Contraindicated in patients with severe liver and kidney dysfunction
Non-insulin antidiabetic agent	Rosiglitazone	Peroxisome proliferator-activated receptor γ	Heart failure; risk of fractures	Contraindicated during pregnancy and lactation
	Acarbose	α-Glucosidase	Abdominal discomfort; flatulence	Contraindicated in patients with chronic gastrointestinal dysfunction
	Metformin	AMP-activated protein kinase	Risk of lactic acidosis; vitamin B12 deficiency	Contraindicated in patients with metabolic acidosis
	Canagliflozin	Sodium-glucose cotransporter 2	Polyuria and urinary tract infection; risk of diabetes ketoacidosis and amputations	Used with caution during urinary system infections

The targets of non-insulin antidiabetic agents mainly include AMP-activated protein kinase (AMPK), sodium-glucose cotransporter 2 (SGLT2), and α-Glucosidase[14]. AMPK agonists (such as metformin) can inhibit liver gluconeogenesis and promote GLUT4 translocation to the PM. SGLT2, a transport protein located in the proximal tubules of the kidneys, dominates the reabsorption of glucose. SGLT2 inhibitors (such as canagliflozin) reduce renal glucose reabsorption, causing increased urinary excretion of glucose and subsequently lowering blood glucose levels. α-Glucosidase, which is located in the mucosa of the small intestine, functions as a hydrolytic enzyme responsible for breaking down dietary carbohydrates into glucose. α-Glucosidase inhibitors (such as acarbose) can delay the absorption of glucose, effectively reducing postprandial blood glucose levels. Although non-insulin antidiabetic agents exhibit potent hypoglycemic effects, they are accompanied by several adverse reactions, including anemia, dizziness, allergic responses, gastrointestinal complications, reproductive system infections, and liver dysfunction (Table 1)[15].

Oral medications exhibit excellent hypoglycemic effects. However, these drugs are accompanied by various adverse reactions that restrict their applicability to a specific population and duration of time. Therefore, it is necessary to explore novel targets for T2DM treatment with a reduced incidence of adverse reactions. In this review, we propose that calcium-permeable ion channels could be powerful therapeutic targets for T2DM treatment via activating AMPK. The details of these calcium ion channels located on cellular organelles or PM are discussed in what follows.

AMPK-ASSOCIATED MEDICATIONS

As summarized in Table 1, currently, there are many targets for T2DM treatment. Among them, AMPK is one of the most powerful targets. AMPK, a heterotrimeric complex, comprises α, β, and γ subunits. The α subunit assumes a catalytic role, encompassing serine/threonine kinase domains with a small N-lobe and a larger C-lobe[16]. AMPK can inhibit TBC1 domain family member 1, which restricts GLUT4 in the cytoplasm, thus facilitating GLUT4 to translocate to the PM[17]. AMPK has also been reported to reduce liver gluconeogenesis, which is significantly elevated in T2DM patients, thus facilitating a decrease in glucose levels (Figure 1)[18].

Figure 1 AMP-activated protein kinase activation in type 2 diabetes mellitus. In patients with type 2 diabetes mellitus, AMP-activated protein kinase promotes glucose transporter isoform 4 translocation from vesicles to the plasma membrane by inhibiting TBC1 domain family member 1, and inhibits liver gluconeogenesis by blocking the conversion of oxaloacetic acid to phosphoenolpyruvate and glucose-6-phosphate to free glucose, leading to reduced blood glucose. APMK: AMP-activated protein kinase; T2DM: Type 2 diabetes mellitus; GLUT4: Glucose transporter isoform 4.

The phosphorylation of the α subunit at Thr172 indicates the activation of AMPK, which is mainly achieved through energy-sensing or calcium signaling[19]. Drugs that activate AMPK via the energy-sensing mechanism include canagliflozin, thiazolidinedione, glibenclamide, and metformin[20-22]. These drugs show powerful potency; however, they are also associated with various adverse effects. For example, metformin, a potent medication for T2DM treatment, inhibits the activity of mitochondrial respiratory complex I, resulting in changes in the AMP/ATP ratio and subsequently activation of AMPK through upstream kinase liver kinase B1. Metformin exhibits a low risk of hypoglycemia, mitigates anorexia, and is compatible with the majority of clinical medications[23]. Unfortunately, patients administered metformin experience significant weight loss and exhibit a deficiency in vitamin B12, and most significantly, long-term application of metformin causes excessive anaerobic respiration and lactic acidosis[24-26]. Symptoms of lactic acidosis include weakness, diarrhea, and emesis, eventually causing organ damage, respiratory insufficiency, and even death[27,28]. Although lactic acidosis is a rare condition, its mortality rate is alarmingly reaching 50%. Therefore, it is crucial to explore potential targets via AMPK activation that retain high potency without causing lactic acidosis. Notably, drugs that activate AMPK through calcium signaling, such as gliclazide and liraglutide, seldom induce lactic acidosis[29,30]. However, the efficacy of gliclazide is inferior to metformin and it has a higher cost[31-33]. Considering the prevention of lactic acidosis, calcium signaling-mediated AMPK activation could be a promising therapeutic pathway for T2DM treatment.

Cellular calcium stores include mitochondria, endoplasmic reticulum (ER), and lysosomes, which control the storage, uptake, and release of calcium. Calcium signaling is mainly released from calcium ion channels located on organelles. These agonists or inhibitors targeting ion channels generally exhibit high specificity. Thus, we propose that calcium ion channels located on organelle membranes could be potential targets for T2DM treatment, and specific agonists or inhibitors of these ion channels could be potential therapeutic drugs for T2DM. In the following section, we summarize the calcium channels that have the potential to be T2DM targets.

CALCIUM-PERMEABLE ION CHANNELS: POTENTIAL TARGETS FOR T2DM?

By virtue of their pivotal roles in maintaining ion homeostasis, ion channels orchestrate organelle functions[34]. However, the current understanding of ion channels and their association with metabolic diseases remains limited. In what follows, we introduce the calcium ion channels located on organelles and the PM and discuss the possibility of these channels participating in AMPK activation (Table 2).

Table 2 Calcium-permeable ion channels.

Channel	Subcellular location	Agonists	Inhibitors	Permeability	Structural features	Regulating AMPK	Role in T2DM
VDAC1	Mitochondria	-	DIDS	Ca2+	The β-barrel architecture is composed of 19 β-strands with an α-helix located horizontally midway within the pore	Change in the AMP: ATP ratio activates AMPK	Mediates ER stress, a characteristic of T2DM
MCU		Spermine	Ruthenium red	Ca2+	Consists of six MCU subunits, an essential MCU regulator, and a solute carrier		Reduces lipid accumulation
NCLX		-	CGP37157	Ca2+/Na+	Three (or four) Na+ exchanged for one Ca2+	-	-
mCHE		-	-	Ca2+/H+	Two H+ exchanged for one Ca2+	-	-
SERCA2/3	ER	Compound A	Thapsigargin	Ca2+	Tetramer with both N2 and C2, resembling a spherical structure.	Calcium accumulation induces AMPK activation	Alleviates heart failure
TRPV1	ER/PM	Capsaicin	A-1165442	Ca2+/Na+	Each monomer in the tetramer exhibits the classic six transmembrane helix architecture of voltage-gated ion channels in its transmembrane domain		Improves glucose uptake
RyRs	ER	Compound 7f	Dantrolene	Ca2+/K+/Na+	Contains four subunits, each with six transmembrane segments but lacking voltage sensors	-	Enhances insulin secretion
IP3Rs	ER	-	Xestospongin C	Ca2+/K+/Na+	Tetramer comprising 2671 residues per subunit with a large amino-terminal cytoplasmic domain followed by a transmembrane domain	-
TRPML1	Lysosome	MK6-83/ML-SA1	ML-SI1/ML-SI3	Ca2+/Fe2+/Zn2+/Na+	A tetramer consisting of four identical 6-transmembrane subunits	Calcium accumulation induces AMPK activation	Enhances insulin pathway
TPC1/2		Riluzole	Trans-Ned 19	Ca2+/Na+	Each subunit has two similar 6-transmembrane helical repeats and two subunits are arranged in pseudo-tandem	-	-
TRPM2	PM	NAD, NAADP	Flufenamic acid	Ca2+/Na+	Four shared homologous regions: A transmembrane domain consisting of six transmembrane helices, a TRP helix, and C-terminal domains containing the conserved TRP domain followed by a coiled-coil region that varies among members	-	Improves glucose uptake
TRPM3		Nifedipine	Promethazine	Ca2+/Mg2+/Zn2+		Calcium accumulation induces AMPK activation	-
TRPM4		CIM0216	-	Ca2+/Na+		-	Improves glucose uptake
TRPM5		-	-	Zn2+/Mg2+/Mn2+		-
TRPM7		Clozapine/naltriben	Ruthenium red	Ca2+/Zn2+/Mg2+/Mn2+		Calcium accumulation induces AMPK activation	Enhances insulin secretion

AMPK: AMP-activated protein kinase; T2DM: Type 2 diabetes mellitus; MCU: Mitochondrial calcium uniporter; NCLX: Na⁺/Ca²⁺ exchanger; mCHE: Mitochondrial Ca²⁺/H⁺ exchanger; TRPV1: Transient receptor potential vanilloid 1; RyRs: Ryanodine receptors; IP3Rs: Inositol 1,4,5-triphosphate receptors.

Calcium-permeable channels on mitochondria

Voltage-dependent anion-selective channel: Voltage-dependent anion-selective channels (VDACs) are widely expressed on the outer mitochondrial membrane and consist of three subtypes: VDAC1-3. The primary structure of the VDAC is the β fold. Modulating the conformation of the β-barrel, which consists of a combination of β-spirals and β-folds, enables precise control over the VDAC gating mechanism. Calcium requires the involvement of VDAC to pass through the outer mitochondrial membrane[35]. The open state of the VDAC maintains a low calcium flux to support mitochondrial respiration, while in its closed state, VDAC enhances calcium permeation, thereby facilitating its opening under conditions of low conductivity[36].

Currently, the majority of studies have focused on VDAC1, while the physiological roles of VDAC2 and VDAC3 remain unclear. VDAC1 is responsible for mitochondrial protein release and mitochondria-mediated cellular apoptosis. Studies have shown that VDAC1 inhibitors disrupt mitochondrial metabolism, leading to an increase in the AMP: ATP ratio and AMPK activation[37]. Moreover, the expression of VDAC1 is upregulated in T2DM patients. The employment of VDAC1 inhibitors enhances insulin secretion and ameliorates hyperglycemia (Table 2)[38].

Mitochondrial calcium uniporter: The mitochondrial calcium uniporter (MCU) is located on the inner mitochondrial membrane, which regulates the uptake of calcium by mitochondria. The MCU complex consists of four components: the pore-forming subunit, the essential MCU regulator, mitochondrial calcium uptake protein 1, and mitochondrial calcium uptake protein 2. To reach the mitochondrial matrix, calcium requires the involvement of the MCU complex[39]. MCU detects increased levels of calcium through the EF-hand domains of the mitochondrial calcium uptake protein, facilitating calcium uptake after its conformational alterations[40].

MCU-mediated calcium uptake is required for the maintenance of hepatic ATP content. The absence of MCU results in a reduction in ATP levels, potentially inducing activation of AMPK. Interestingly, contrary to expectations, studies have shown that the absence of MCU leads to a significant reduction in AMPK activation levels[41]. Although the precise relationship between AMPK and MCU remains to be elucidated, MCU is significantly decreased in T2DM patients[42]. MCU restoration effectively reduces liver lipid accumulation and alleviates diabetic cardiomyopathy, a complication of T2DM, highlighting its potential as a therapeutic target for T2DM (Table 2)[43].

Mitochondrial Na⁺/Ca²⁺ exchanger and mitochondrial Ca²⁺/H⁺ exchanger: Mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) and mitochondrial Ca²⁺/H⁺ exchanger (mCHE) have been identified as mitochondrial calcium efflux systems for ion exchange. Both NCLX and mCHE are capable of facilitating the release of calcium from mitochondria[44]. NCLX or mCHE functions as a transporter through the formation of hexameric structures, facilitating ion exchange and calcium release. NCLX facilitates Na⁺/Ca²⁺ exchange by mediating the interaction between multiple residues and ions[45]. Although research has demonstrated the neuroprotective effects of NCLX, it remains unclear whether calcium release from NCLX is implicated in AMPK activation or T2DM treatment[46]. In hepatocytes, the activity of NCLX is relatively low, while the involvement of mCHE is essential for calcium ion exchange and ATP generation[47]. However, the precise structure and physiological functions of mCHE remain unknown.

Briefly, mitochondrial ion channels such as MCU and VDAC are known to be associated with AMPK and T2DM treatment. However, the roles of ion channels, such as NCLX and mCHE in T2DM treatment have not been investigated although they have the potential to activate AMPK.

Calcium-permeable ion channels on the ER

Sarcoplasmic/ER calcium ATPase: Sarcoplasmic/ER calcium ATPase (SERCA) is responsible for uptake of calcium into the ER lumen, thereby maintaining intracellular calcium homeostasis. SERCA isoforms are encoded by three genes, SERCA 1, 2, and 3. These subtypes demonstrate specificity in terms of tissue and development. SERCA1 is primarily expressed in skeletal muscle, while SERCA2 exhibits predominant expression in cardiac muscle and is co-expressed with SERCA3 in various tissues. They are P-type ion-activated ATPases, which are activated when the intracellular calcium concentration exceeds 10^-4 mmol/L[48]. Calcium binds to the E2 domain of SERCA, inducing its phosphorylation and causing conformational changes, thereby entering the ER[49].

SERCA2a, a subtype of SERCA expressed in the heart, is closely related to heart failure, which is a complication of T2DM[50]. The expression of SERCA2a is downregulated in heart tissue. Restoration of SERCA2a expression holds potential for the treatment of heart failure[51]. Reductions in the expression of SERCA2b and SERCA3 have been observed in the islet β cells of T2DM patients, resulting in impaired insulin secretion[52,53]. Therefore, restoring SERCA2/3 levels may enhance insulin secretion, suggesting a potential therapeutic strategy. Treatment with saikosaponin-d, an inhibitor of SERCAs, causes intracellular calcium accumulation and CaMKKβ/AMPK activation (Table 2)[54]. However, the potential of SERCA-induced AMPK activation remains to be elucidated in T2DM treatment.

Ryanodine receptors and inositol 1,4,5-triphosphate receptors: Ryanodine receptors (RyRs) and inositol 1,4,5-triphosphate receptors (IP3Rs) are calcium release channels. These channels are activated by low cytoplasmic calcium concentrations and assemble into tetramers that allow the passage of calcium[55]. RyRs and IP3Rs are widely expressed, with each encompassing three distinct isoforms: RyR1-3 and IP3R1-3. The physiological roles of these subtypes remain unclear. The structure of RyRs primarily comprises α-helical solenoid regions, along with EF hand-like domains and transmembrane regions resembling voltage-gated ion channels. IP3Rs exhibit a similar structural composition to that of RyRs, featuring six transmembrane helices and inositol triphosphate binding domains, but they lack EF hand-like domains[56]. The activation of RyRs and IP3Rs by calcium facilitates their direct binding with calcium, resulting in the subsequent calcium release.

RyRs release a large amount of calcium from the ER into the cytoplasm during muscle contractions. The antagonist dantrolene directly acts as a skeletal muscle relaxant by exploiting this mechanism. RyRs are commonly associated with hyperthermia and central core disease, while IP3Rs are more associated with cancer[57]. Interestingly, MCU takes up the calcium released from these channels for ATP production, further enhancing insulin secretion and treating T2DM (Table 2)[58]. However, there is currently no evidence to suggest a direct correlation between calcium release mediated by these two channels and the activation of AMPK or T2DM treatment.

Transient receptor potential vanilloid 1: Transient receptor potential vanilloid 1 (TRPV1) exhibits sensitivity to various stimuli[59]. The vast majority of functional TRPV1 is located on the ER[60]. TRPV1 is a tetramer formed by subunits with six transmembrane segments (S1-S6). The binding sites of selective filters exhibit an affinity for calcium[61]. Temperature modulation is observed in TRPV1[62]. TRPV1 is involved in nociception, thermoregulation, and the modulation of cough[63]. Research has shown that AMPK activation and T2DM treatment can be facilitated by TRPV1-released calcium from the ER (Table 2)[64].

Inhibiting TRPV1 reduces the intracellular calcium concentration and the phosphorylation of CaMKKβ and AMPK. The absence of TRPV1 causes several T2DM complications[65-67]. In contrast, capsaicin, piperine, and total sesquiterpene glycosides induce TRPV1-mediated CaMKKβ and AMPK activation to promote GLUT4 translocation to the PM and improve glucose homeostasis (Table 2)[68-71]. Interestingly, some researchers also believe that TRPV1 mediates the secretion of GLP-1 to regulate glucose homeostasis[72].

Calcium-permeable channels on lysosomes

Transient receptor potential mucolipins: There are two subtypes of transient receptor potential mucolipins (TRPMLs) in humans: TRPML1 and TRPML2. TPRML1 is a calcium-permeable ion channel localized within lysosomes. Encoded by the MCOLN1 gene, it exhibits widespread expression in various tissues, including hepatic tissue. TRPML2 is predominantly observed in lymphoid and bone marrow tissues. The structure of TRPMLs is similar to that of other TRP channels, including six transmembrane helices (S1-S6), two pore helices (PH1 and PH2), and a luminal domain. The TRPML agonist ML-SA1 binds to hydrophobic cavities formed by the adjacent PH1, S5, and S6[73]. The tetramer formed by the first and second transmembrane domains of TRPMLs actively participates in ion transport[74].

TRPMLs regulate lysosomal ion homeostasis, membrane trafficking, and signal transduction. The absence of TRPML1 causes lysosomal storage diseases such as type IV mucolipidosis[75]. TRPML2 is associated with inflammation and immunity[76]. Notably, recent research demonstrated that TRPML1 modulates autophagy in a TFEB-independent manner involving CaMKKβ/AMPK activation[77]. The activation of the insulin pathway by artemisia leaf extract is dependent on TRPML1 (Table 2)[78].

Two-pore channels: The two-pore channels (TPCs) are calcium-permeable channels localized on the membranes of lysosomes. TPCs are involved in various physiological processes, such as cellular growth and metabolism. The TPC family consists of two human members, namely TPC1 and TPC2. TPC1/2 function as homodimers, with each subunit comprising 12 transmembrane segments[79]. The EF domain of TPC1/2 connects these transmembrane fragments and contains two calcium-binding sites[80]. TPC1/2 are involved in the regulation of multiple internal lysosomal transport pathways, and thus the absence of TPC1/2 may result in the development of lysosomal storage diseases[81]. Recent research has demonstrated that TPC1/2 serve as a target for treating pro-inflammatory diseases such as allergic hypersensitivity. Notably, TPC1/2 are required in glutamate-mediated AMPK activation. The TPC1/2 inhibitor Ned-19 effectively inhibited this process (Table 2)[82]. However, the investigation of the relationship between lysosomal ion channels and AMPK-mediated T2DM treatment remains limited.

Calcium-permeable channels on the PM

Transient receptor potential melastatin: There are various calcium ion channels on the PM, which are responsible for intracellular and extracellular ion exchange. This article only focuses on transient receptor potential melastatin (TRPM), which has been reported to be involved in T2DM. TRPMs, located on the PM, are crucial for sensory physiology. Members of the TRPM family are extensively expressed in the islet β cells, heart, and kidneys. The TRPM family comprises eight members, and only TRPM4 and 5 are not calcium-permeable. However, TRPM4 and 5 can be activated by intracellular calcium accumulation. The subunits of TRPM members consist of a substantial number of amino acids, rendering them the largest proteins within the TRP superfamily. TRPM members interact with calmodulin, a calcium-binding protein, controls calcium homeostasis[83]. They are generally composed of six transmembrane helical domains with a conserved calcium-binding site[84]. TRPM members have been implicated in various physiological processes[85]. For example, TRPM1 plays a pivotal role in melanin metabolism, TRPM2 serves as a crucial factor in oxidative stress-induced cell death, TRPM3 is implicated in the pathogenesis of clear cell renal cell carcinoma, TRPM4 has the potential to enhance interleukin-2 production, TRPM5 is involved in the development of T2DM, both TRPM6 and TRPM7 modulate the response to sepsis, and TRPM8 is a clinical target for prostate cancer treatment[86]. Here, we focus on their potential association with AMPK and T2DM.

TRPM2, TRPM3, and TRPM7 are associated with AMPK activation. Silencing TRPM2 leads to a decrease in ATP levels and activates AMPK. In TRPM2 knockout cells, abscisic acid-mediated AMPK activation improves glucose uptake and is independent of the insulin pathway[87]. In contrast, activation of TRPM3 and TRPM7 induces intracellular calcium accumulation, thereby enhancing the phosphorylation levels of CaMKKβ and AMPK[88,89]. Clotrimazole and glibenclamide (inhibitors of TRPM4) inhibit AMPK-mediated muscle cell hyperpolarization[90]. Additionally, TRPM2, TRPM4, and TRPM5 regulate insulin secretion by perceiving the intracellular calcium levels (Table 2)[91]. Currently, TRPMs are reported to induce AMPK activation; however, further investigation is required to elucidate whether TRPM-mediated AMPK activation causes adverse reactions in the treatment of T2DM.

CHALLENGES ENCOUNTERED IN DEVELOPING ION CHANNEL DRUGS

Targeting calcium channels in the treatment of T2DM is promising (Figure 2). However, there are still many challenges to overcome: (1) The structures and functions of these channels remain elusive; (2) Highly specific agonists and inhibitors are not available for many of these channels; (3) Agonists and inhibitors of these channels exhibit cytotoxicity, and thus require further development; and (4) When more than one calcium channel is present on the same organelle, how these channels work remains unclear. Therefore, developing efficient and non-toxic agonists and inhibitors for these channels is imperative. Additionally, extensive research is required to elucidate the structure and function of other ion channels.

CONCLUSION

In this review, we summarize 15 calcium ion channels that could be potential targets for T2DM treatment via AMPK (Figure 2). Among them, seven (VDAC1, MCU, SERCA, TRPV1, TRPML1, TRPM3, and TRPM7) have been specifically reported to be associated with AMPK activation. VDAC1 and MCU activate AMPK through the energy-sensing mechanism, while SERCA, TRPV1, TRPML1, TRPM3, and TRPM7 activate AMPK through calcium signaling. Moreover, TRPV1, SERCA, and TRPML1 have already been proven to activate AMPK and alleviate the phenotype of T2DM. In addition, there are other ion channels, such as potassium ion channels, that reportedly play a role in the treatment of T2DM[92]. Since this is not the focus of this article, we have not discussed these channels in this review. In summary, targeting calcium-permeable channels is a very promising direction in the exploration of new drugs for T2DM, but extensive studies are required in this field.

Figure 2 Potential roles of calcium-permeable ion channels in glucose uptake. A working model to illustrate the possible role of calcium ion channels in glucose uptake. Various calcium ion channels located on various organelles and the plasma membrane can increase the cytosolic calcium release, then activating calmodulin-dependent protein kinase 2/AMP-activated protein kinase pathway via phosphorylation of the Thr172 site and leads to increased glucose uptake, thus treating type 2 diabetes mellitus (T2DM). Specific agonists could be potential therapeutic drugs for T2DM. PM: Plasma membrane; ER: Endoplasmic reticulum.