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

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.