Ionic mechanisms in pancreatic β cell signaling

Shao-Nian Yang; Yue Shi; Guang Yang; Yuxin Li; Jia Yu; Per-Olof Berggren

doi:10.1007/s00018-014-1680-6

. 2014 Jul 23;71(21):4149–4177. doi: 10.1007/s00018-014-1680-6

Ionic mechanisms in pancreatic β cell signaling

Shao-Nian Yang ^1,^3,^✉, Yue Shi ¹, Guang Yang ^1,², Yuxin Li ³, Jia Yu ¹, Per-Olof Berggren ¹

PMCID: PMC11113777 PMID: 25052376

Abstract

The function and survival of pancreatic β cells critically rely on complex electrical signaling systems composed of a series of ionic events, namely fluxes of K⁺, Na⁺, Ca²⁺ and Cl⁻ across the β cell membranes. These electrical signaling systems not only sense events occurring in the extracellular space and intracellular milieu of pancreatic islet cells, but also control different β cell activities, most notably glucose-stimulated insulin secretion. Three major ion fluxes including K⁺ efflux through ATP-sensitive K⁺ (K_ATP) channels, the voltage-gated Ca²⁺ (Ca_V) channel-mediated Ca²⁺ influx and K⁺ efflux through voltage-gated K⁺ (K_V) channels operate in the β cell. These ion fluxes set the resting membrane potential and the shape, rate and pattern of firing of action potentials under different metabolic conditions. The K_ATP channel-mediated K⁺ efflux determines the resting membrane potential and keeps the excitability of the β cell at low levels. Ca²⁺ influx through Ca_V1 channels, a major type of β cell Ca_V channels, causes the upstroke or depolarization phase of the action potential and regulates a wide range of β cell functions including the most elementary β cell function, insulin secretion. K⁺ efflux mediated by K_V2.1 delayed rectifier K⁺ channels, a predominant form of β cell K_V channels, brings about the downstroke or repolarization phase of the action potential, which acts as a brake for insulin secretion owing to shutting down the Ca_V channel-mediated Ca²⁺ entry. These three ion channel-mediated ion fluxes are the most important ionic events in β cell signaling. This review concisely discusses various ionic mechanisms in β cell signaling and highlights K_ATP channel-, Ca_V1 channel- and K_V2.1 channel-mediated ion fluxes.

Keywords: Calcium mobilization, Electrophysiology, Exocytosis, Ion channel, Pancreatic endocrine cell, Protein kinase

Introduction

Pancreatic β cells are a major cellular component of the islets of Langerhans. These cells are exquisitely sensitive to glucose. They secrete insulin, which is the only hormone capable of lowering blood glucose in the body, and thus play a unique role in glucose homeostasis. To timely and accurately release insulin in response to changes in blood glucose levels, a series of ionic events, namely fluxes of K⁺, Na⁺, Ca²⁺ and Cl⁻ across the β cell membranes occur [1, 2]. The electrically excitable β cell employs these ion fluxes to constitute complex ionic mechanisms that sense events occurring in its extracellular space and intracellular milieu and control different β cell activities [1–8]. This is because these ionic mechanisms are sooner or later coupled to the versatile intracellular signal Ca²⁺ that participates in the regulation of all known molecular and cellular events, such as exocytosis, endocytosis, protein phosphorylation, gene expression, metabolism, differentiation, growth and even cell death [7, 8]. This review summarizes current knowledge of various ionic mechanisms and their building blocks, ion channels, in β cell signaling.

Among the complex ionic mechanisms, ion fluxes through ATP-sensitive K⁺ (K_ATP) channels, voltage-gated Ca²⁺ (Ca_V) channels and voltage-gated K⁺ (K_V) channels are the most important ionic events in β cell signaling. K_ATP, Ca_V and K_V channels take center stage in generation of electrical activities to control glucose-stimulated insulin secretion. Disturbances in these three ion channel-mediated ion events inevitably impair β cell function and survival, and thereby contributing to the pathogenesis of diabetes. This review highlights the K_ATP, Ca_V and K_V channel-mediated ionic events, their functional significances and the general structure and important regulation of K_ATP channels, Ca_V1 channels and K_V2.1 channels on top of the general discussion of the various ionic mechanisms.

Ionic mechanisms operate in various subcellular compartments of the β cell

The complexity of ionic mechanisms relies on the diversity of their elementary building blocks, ion channels. The β cell accommodates more than 16 ion channel families consisting of about 60 different types of ion channels responsible for complex ionic mechanisms (Table 1) [1, 2, 5–80]. We summarize these ion channels with emphasis on their ion selectivity, activators, blockers and function in Table 1 to provide a concise guide to β cell ion channel research. These ion channels operate not only in the β cell plasma membrane but also in subcellular organelle membranes to generate sophisticated electrical activities and specific ionic milieus, such as cytosolic free calcium concentration ([Ca²⁺]_i) and pH, for complex β cell signaling.

Table 1.

Ion channel families and their members in different subcellular compartments of the pancreatic β cell

Families	Members	Ion selectivity	Activators	Blockers	Function in the β cell	References
Plasma membrane
Voltage-gated sodium (Na_V) channel	Na_V1.3 channel	Na⁺	Batrachotoxin, veratridine	Saxitoxin, tetrodotoxin	–	[9, 10]
	Na_V1.6 channel	Na⁺	Batrachotoxin, veratridine	Saxitoxin, tetrodotoxin	Action potential upstroke in the human β cell	[1, 10–13]
	Na_V1.7 channel	Na⁺	Batrachotoxin, veratridine	Saxitoxin, tetrodotoxin	Action potential upstroke in the human β cell	[1, 10–13]
Voltage-gated calcium (Ca_V) channel	Ca_V1.2 channel	Ca²⁺	FPL64176, (S)-(−)-Bay K8644, SZ(+)-(S)-202-791	Calciseptine, diltiazem, nifedipine, verapamil	Action potential upstroke, Ca²⁺ signaling, insulin secretion	[1, 7, 8, 11, 13–16]
	Ca_V1.3 channel	Ca²⁺	(S)-(−)-Bay K8644	Nifedipine, verapamil	Action potential upstroke, Ca²⁺ signaling, insulin secretion
	Ca_V2.1 channel	Ca²⁺	–	ω-Agatoxin IVA	Action potential upstroke, Ca²⁺ signaling, insulin secretion
	Ca_V2.2 channel	Ca²⁺	–	ω-Conotoxin GVIA	Action potential upstroke, Ca²⁺ signaling, insulin secretion
	Ca_V2.3 channel	Ca²⁺	–	SNX 482	Action potential upstroke, Ca²⁺ signaling, insulin secretion
	Ca_V3.1 channel	Ca²⁺	–	Mibefradil, NNC 55-0396, TTA-A2, TTA-P2, Z944	Action potential upstroke, Ca²⁺ signaling, insulin secretion
	Ca_V3.2 channel	Ca²⁺	–	Mibefradil, NNC 55-0396, TTA-A2, TTA-P2, Z944	Action potential upstroke, Ca²⁺ signaling, insulin secretion
Voltage-gated potassium (K_V) channel	K_V1.4	K⁺	–	α-Dendrotoxin, margatoxin, noxiustoxin, tetraethylammonium, 4-aminopyridine	–	[1, 6, 10, 11, 13, 17–22]
	K_V1.5	K⁺	–	α-Dendrotoxin, margatoxin, noxiustoxin, tetraethylammonium, 4-aminopyridine	–
	K_V1.6	K⁺	–	α-Dendrotoxin, margatoxin, noxiustoxin, tetraethylammonium, 4-aminopyridine	–
	K_V2.1	K⁺	–	Stromatoxin-1, tetraethylammonium	Action potential downstroke in the rodent β cell
	K_V2.2	K⁺	–	Stromatoxin-1, tetraethylammonium	–
	K_V3.2	K⁺	–	4-Aminopyridine, tetraethylammonium, sea anemone toxin BDS-I	–
	K_V6.2	Modifier/silencer	–	–	–
	K_V9.3	Modifier/silencer	–	–	–
ATP-sensitive potassium (K_ATP) channel	Kir6.2/SUR1 channel	K⁺	Diazoxide	ATP/ADP ratio, sulfonylureas, glinides	Resting membrane potential	[1, 2, 5, 13, 15, 23]
Calcium-activated potassium (K_Ca) channel	BK channel (K_Ca1.1, KCNMA1)	K⁺	Voltage-dependent, [Ca²⁺]_i, NS004, NS1619	Charybdotoxin, iberiotoxin, tetraethylammonium	Modulation of action potential shape and firing, action potential downstroke in the human β cell	[1, 10, 11, 13, 15]
	SK1 channel (K_Ca2.1, KCNN1)	K⁺	[Ca²⁺]_i	Apamin? UCL 1684	Repolarization of plateau potentials, [Ca²⁺]_i oscillation	[1, 6, 24–28]
	SK2 channel (K_Ca2.2, KCNN2)	K⁺	[Ca²⁺]_i	Apamin, UCL 1684	Repolarization of plateau potentials, [Ca²⁺]_i oscillation
	SK3 channel (K_Ca2.3, KCNN3)	K⁺	[Ca²⁺]_i	Apamin, UCL 1684	Repolarization of plateau potentials, [Ca²⁺]_i oscillation
	IK channel (K_Ca3.1, KCNN4, SK4)	K⁺	[Ca²⁺]_i	Charybdotoxin	Repolarization of plateau potentials, [Ca²⁺]_i oscillation
TRP channel	TRPA1	Non-selective/Ca²⁺-permeable	Thermosensitive (<17 °C)? voltage-dependent, [Ca²⁺]_i, mechanical stress, isothiocyanates, icilin, allicin, H₂O₂, 1,4-dihydropyridines	Ruthenium red	Ca²⁺ influx, depolarization, insulin secretion	[10, 29, 30]
	TRPC1	Non-selective/Ca²⁺-permeable	Membrane stretch, store depletion, NO-mediated cysteine S-nitrosylation	2-APB, Gd³⁺, La³⁺, SKF96365	–	[10, 30, 31]
	TRPC3	Non-selective/Ca²⁺-permeable	Diacylglycerols	2-APB, Gd³⁺, La³⁺, Ni²⁺, SKF96365, pyrazole-3	–	[10, 32]
	TRPC4	Non-selective/Ca²⁺-permeable	NO-mediated cysteine S-nitrosylation, G_q-PLC pathways, La³⁺ (μM)	2-APB, La³⁺ (mM), niflumic acid, SKF96365	–	[10, 30, 31]
	TRPC5	Non-selective/Ca²⁺-permeable	NO-mediated cysteine S-nitrosylation? extracellular H⁺, [Ca²⁺]_i, La³⁺ (μM)	2-APB, chlorpromazine, flufenamic acid, La³⁺ (mM), SKF96365	–	[10, 32]
	TRPC6	Non-selective/Ca²⁺-permeable	G_q-PLC pathways/diacylglycerols, 2,4 diahexanxoylphloroglucinol, flufenamate, hyperforin	2-APB, amiloride, Cd²⁺, Gd³⁺, extracellular H⁺, SKF96365	–	[10, 30, 31]
	TRPM2	Non-selective/Ca²⁺-permeable	Thermosensitive (~35 °C), H₂O₂, [Ca²⁺]_i, ADPR, cADPR, arachidonic acid	Extracellular H⁺, Zn²⁺, 2-APB, clotrimazole	Ca²⁺ influx, insulin secretion, H₂O₂-induced apoptosis	[10, 30, 31, 33, 34]
	TRPM3	Non-selective/Ca²⁺-permeable	Thermosensitive (15–25 °C), hypotonic cell swelling, steroid hormones, nifedipine	Intracellular Mg²⁺, extracellular Na⁺, 2-APB, Gd³⁺, La³⁺	Ca²⁺ influx, Zn²⁺ influx	[10, 30, 31, 35, 36]
	TRPM4	Non-selective/Ca²⁺-impermeable	Voltage-dependent, thermosensitive (15–25 °C at +25 mV), [Ca²⁺]_i (transient activation), decavanadate	9-Phenanthrol, clotrimazole, flufenamic acid, intracellular spermine, ATP, ADP, AMP, adenosine	Depolarization, insulin secretion?	[10, 30, 31, 37, 38]
	TRPM5	Non-selective/Ca²⁺-impermeable	Voltage-dependent, thermosensitive (15–25 °C at −75 mV), [Ca²⁺]_i (transient activation)	Flufenamic acid, intracellular spermine, extracellular H⁺	Depolarization, [Ca²⁺]_i oscillation, insulin secretion	[10, 30, 31, 39, 40]
	TRPV1	Non-selective/Ca²⁺-permeable	Voltage-dependent, thermosensitive (>43 °C), NO-mediated cysteine S-nitrosylation, camphor, capsaicin, extracellular H⁺	2-APB, allicin, ruthenium red	Insulin secretion	[10, 30, 31, 41]
	TRPV2	Non-selective/Ca²⁺-permeable	Thermosensitive (>35 °C), voltage, 2-APB	Amiloride, ruthenium red, SKF96365	Ca²⁺ influx, insulin secretion	[10, 30, 31, 42]
	TRPV4	Non-selective/Ca²⁺-permeable	Constitutively active, thermosensitive (>24–32 °C), mechanical stimuli, NO-mediated cysteine S-nitrosylation	Gd³⁺, La³⁺, ruthenium red	Ca²⁺ influx, apoptosis	[10, 30, 31, 43]
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel	HCN1 channel	Na⁺, K⁺	cAMP, cGMP	Cs⁺, ivabradine, ZD7288	Insulin secretion under hypokalemic conditions	[10, 44, 45]
	HCN2 channel	Na⁺, K⁺	cAMP, cGMP	Cs⁺, ivabradine, ZD7288	Insulin secretion under hypokalemic conditions
	HCN3 channel	Na⁺, K⁺	–	Cs⁺, ivabradine, ZD7288	Insulin secretion under hypokalemic conditions
	HCN4 channel	Na⁺, K⁺	cAMP, cGMP	Cs⁺, ivabradine, ZD7288	Insulin secretion under hypokalemic conditions
Purinergic P2X receptor channel	P2X₁ receptor channel	Non-selective/Ca²⁺-permeable	ATP, αβ-meATP, 2-meSATP	Suramin, PPADS	Ca²⁺ influx, depolarization, insulin secretion	[46, 47]
Purinergic P2X receptor channel	P2X₃ receptor channel	Non-selective/Ca²⁺-permeable	ATP, αβ-meATP, 2-meSATP	Suramin, PPADS	Ca²⁺ influx, depolarization, insulin secretion	[46, 47]
Glutamate receptor ion channel	α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channel	Non-selective/Ca²⁺-permeable	Glutamate, AMPA	NBQX, CNQX	Ca²⁺ influx, depolarization, insulin secretion	[48, 49]
	Kainate receptor channel	Non-selective/Ca²⁺-permeable	Glutamate, kainate	NS102, CNQX	Ca²⁺ influx, depolarization, insulin secretion
	N-methyl-d-aspartate (NMDA) receptor channel	Non-selective/Ca²⁺-permeable	Glutamate, aspartate, NMDA, voltage-dependent	Mg²⁺, Zn²⁺, amantadine, MK-801	Ca²⁺ influx, depolarization, insulin secretion
γ-Aminobutyric acid (GABA)_A receptor ion channel	–	Cl⁻	GABA, muscimol, benzodiazepine	Bicuculline, picrotoxin, gabazine	Depolarization, insulin secretion	[50–52]
Chloride channel	Volume-regulated anion channel	Cl⁻	Swelling, ATP, cAMP, glyburide, tolbutamide, glibenclamide	DIDS, NPPB, DCPIB, tenidap	Depolarization, insulin secretion	[1, 53–56]
Chloride channel	CFTR chloride channel	Cl⁻	PKA phosphorylation, bacterial enterotoxins	Glibenclamide, diphenylamine-2-carboxylate, NPPB, niflumic acid	–	[57, 58]
Endoplasmic reticulum/nuclear envelope
ATP-sensitive potassium (K_ATP) channel	Kir6.2/SUR1 channel	K⁺	Diazoxide	ATP/ADP ratio, tolbutamide	Nuclear Ca²⁺ signaling	[59–61]
Inositol 1,4,5-trisphosphate receptor (IP₃R) ion channel	IP₃R1 channel	Ca²⁺	IP₃, cytosolic ATP, [Ca²⁺]_i, adenophostin A	Heparin, caffeine, decavanadate, PIP₂, xestospongin C	Ca²⁺ release from intracellular stores, Ca²⁺ signaling, insulin secretion	[62, 63]
	IP₃R2 channel	Ca²⁺	IP₃, [Ca²⁺]_i, adenophostin A	Heparin, decavanadate	Ca²⁺ release from intracellular stores, Ca²⁺ signaling, insulin secretion
	IP₃R3 channel	Ca²⁺	IP₃, [Ca²⁺]_i	Heparin, decavanadate	Ca²⁺ release from intracellular stores, Ca²⁺ signaling, insulin secretion
RyR ion channel	RyR1 channel	Ca²⁺	[Ca²⁺]_i, voltage-dependent, ATP, caffeine, ryanodine (nM–μM)	Mg²⁺, dantrolene, ryanodine (>100 μM), ruthenium red, [Ca²⁺]_i (>100 μM)	Ca²⁺ release from intracellular stores, Ca²⁺ signaling, insulin secretion	[64, 65]
	RyR2 channel	Ca²⁺	[Ca²⁺]_i, ATP, caffeine, ryanodine (nM–μM)	Mg²⁺, ryanodine (>100 μM), ruthenium red, [Ca²⁺]_i (>1 mM)	Ca²⁺ release from intracellular stores, Ca²⁺ signaling, insulin secretion
	RyR3 channel	Ca²⁺	[Ca²⁺]_i, ATP, caffeine, ryanodine (nM–μM)	Mg²⁺, dantrolene, ruthenium red, [Ca²⁺]_i (>1 mM)	Ca²⁺ release from intracellular stores, Ca²⁺ signaling, insulin secretion
Insulin granule
ATP-sensitive potassium (K_ATP) channel	Kir6.2/SUR1 channel	–	–	–	–	[66]
Chloride channel	ClC-3 Cl⁻ channel	Cl⁻	ATP/ADP ratio	DIDS, ClC-3 Cl⁻ channel antibody	Acidification and priming of insulin granules	[67–70]
TRP channel	TRPV5	highly Ca²⁺-permeable	Constitutively active/inactivated by [Ca²⁺]_i	Econazole, Mg²⁺, miconazole, ruthenium red	Ca²⁺ mobilization from insulin granules?	[10, 30, 31]
Inositol 1,4,5-trisphosphate receptor (IP₃R) ion channel	IP₃R3 channel?	–	–	–	Ca²⁺ mobilization from insulin granules?	[71]
RyR ion channel	–	Ca²⁺	Caffeine, 4-chloro-3-ethylphenol, cADPR	–	Ca²⁺ mobilization from insulin granules	[72]
Chromogranin-positive/insulin-negative granule
ATP-sensitive potassium (K_ATP) channel	Kir6.2/SUR1 channel	–	–	–	Glucose-induced recruitment of K_ATP channels from intracellular compartments to the plasma membrane	[73]
Mitochondrion
Voltage-dependent anion channel (VDAC)	VDAC1 channel	ATP, ADP, pyruvate, malate, and other metabolites, ions	Bax	Bcl-xL, NADH	Metabolite transport, ion transport	[74–76]
	VDAC2 channel	ATP, ADP, pyruvate, malate, and other metabolites, ions	Bax	Bcl-xL, NADH	Metabolite transport, ion transport
	VDAC3 channel	ATP, ADP, pyruvate, malate, and other metabolites, ions	Bax	Bcl-xL, NADH	Metabolite transport, ion transport
Mitochondrial Ca²⁺ uniporter (MCU)	–	Ca²⁺, other divalent cations	Ca²⁺, voltage-dependent, spermine	Mg²⁺, ruthenium red	Mitochondrial Ca²⁺ uptake	[76–78]
ATP-sensitive potassium (K_ATP) channel	–	K⁺	GTP, GDP, diazoxide	ATP, ADP, glibenclamide, 5-hydroxydecanoate	Dissipation of the inner mitochondrial membrane potential	[79, 80]
Lysosome
TRP channel	TRPM2	Non-selective/Ca²⁺-permeable	Heat ~35 °C, H₂O₂, [Ca²⁺]_i, ADPR, cADPR, arachidonic acid	Extracellular H⁺, Zn²⁺, 2-APB, clotrimazole	Ca²⁺ mobilization from lysosome, H₂O₂-induced apoptosis	[10, 30, 31, 33]

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ADP adenosine 5′-diphosphate, ADPR adenosine 5′-diphosphate ribose, AMP adenosine 5′-monophosphate, 2-APB 2-aminoethoxydiphenyl borate, ATP adenosine 5′-triphosphate, αβ-meATP αβ-methyleneadenosine 5′-triphosphate, BK large conductance calcium-activated potassium, cADPR cyclic adenosine 5′-diphosphate ribose, cAMP cyclic adenosine 3′,5′-monophosphate, [Ca ²⁺ ] _i cytosolic free calcium concentration, cGMP cyclic guanosine 3′,5′-monophosphate, CNQX 6-cyano-7-nitroquinoxaline-2,3-dione, DCPIB 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on5-yl)oxobutyric acid, DIDS 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, FPL64176 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxlic acid methyl ester, GDP guanosine diphosphate, GTP guanosine triphosphate, IK intermediate conductance calcium-activated potassium, IP ₃ inositol 1,4,5-trisphosphate, Kir inward rectifier K⁺, MK-801 (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate, 2-meSATP 2-methylthioadenosine 5′-triphosphate, NADH reduced nicotinamide adenine dinucleotide, NBQX 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, NNC 55-0396 (1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride, NO nitric oxide, NPPB 5-Nitro-2-(3-phenylpropylamino)benzoic acid, NS004 1-(2-hydroxy-5-chlorophenyl)-5-trifluoromethyl-2-benzimidazolone, NS102 6,7,8,9-tetrahydro-5-nitro-1H-benz[g]indole-2,3-dione 3-oxime, NS1619 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one, PIP ₂ phosphatidylinositol 4,5-bisphosphate, PKA protein kinase A, PLC phospholipase C, PPADS pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid, (S)-(-)-Bay K8644 S-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester, SK small conductance calcium-activated potassium, SKF96365 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl]imidazole, SNX 482 41 amino acid peptide (GVDKAGCRYMFGGCSVNDDCCPRLGCHSLFSYCAWDLTFSD), SUR sulfonylurea receptor, SZ(+)-(S)-202-791 isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-3-pyridinecarboxylate, TTA-A2 (R)-2-(4-cyclopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide, TTA-P2 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide, UCL 1684 6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-metheno-7H-dibenzo [b,n] [1, 5, 12, 16] tetraazacyclotricosine-5,13-diium dibromide, ZD7288 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride, Z944 N-((1-(2-(tert-butylamino)-2-oxoethyl) piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride, – unknown, ? controversy

K_ATP, Ca_V and K_V channel-mediated ion fluxes

The β cell plasma membrane is equipped with about 50 different types of ion channels (Table 1). The K_ATP channel-mediated K⁺ efflux sets the resting membrane potential and maintains low levels of β cell excitability (Table 1; Fig. 1) [1, 2, 15, 23]. Ca²⁺ influx through Ca_V channels, mainly Ca_V1.2 channels, contributes to the upstroke or depolarization phase of the action potential and controls all known molecular and cellular activities in the β cell, and in particular glucose-stimulated insulin secretion (Table 1; Fig. 1) [2, 7, 8, 14]. K⁺ efflux mediated by K_V2.1 delayed rectifier K⁺ channels, a predominant form of β cell K_V channels, causes the downstroke or repolarization phase of the action potential and acts as a brake for insulin secretion (Table 1; Fig. 1) [2, 6]. These three critical ion fluxes in β cell signaling have attracted extraordinary attention and are discussed in detail in the later sections.

Ion fluxes through transient receptor potential (TRP) channels

In the β cell plasma membrane, there is a diverse repertoire of ion channels to assemble sophisticated ionic mechanisms [1]. In addition to K_ATP, Ca_V and K_V channels, more than a dozen members of the TRP channel family exist in the β cell plasma membrane (Table 1) [30, 31]. Most β cell TRP channels are non-selectively permeable to cations including Na⁺, Ca²⁺ and Mg²⁺ [10, 30, 31]. Ca²⁺-impermeable TRPM4 and TRPM5 channels as well as highly Ca²⁺-permeable TRPV5 channels are also present in the β cell [30, 31]. β Cell TRP channels activate in response to chemical challenges, mechanical stimuli or thermal alterations in a voltage-dependent or voltage-independent manner [10, 30, 31]. However, it is still a challenging task to match different physiological scenarios to selective activation of β cell TRP channels. Cation influx through β cell TRP channels not only depolarizes the β cell plasma membrane to increase β cell excitability, but also contributes to [Ca²⁺]_i to regulate Ca²⁺-dependent cellular processes including glucose-stimulated insulin secretion [10, 30, 31]. Table 1 lists basic information about β cell TRP channels. Here we highlight TRPM2 channels to exemplify the physiological and pathophysiological significance of β cell TRP channels. TRPM2 channels have been demonstrated to bring about important ionic events in regulation of glucose-stimulated insulin secretion [10, 30, 31, 33, 34]. TRPM2 knockout mice display glucose intolerance accompanied by insufficient elevation in plasma insulin levels. This is attributed to decreased [Ca²⁺]_i response in TRPM2-null β cells and impaired insulin secretion from TRPM2-deficient islets exposed to high glucose [34]. Indeed, arachidonic acid, cADPR, ADPR, H₂O₂, [Ca²⁺]_i and temperature changes have been shown to activate β cell TRPM2 channels [10, 30, 31, 33]. However, it appears that glucose employs a set of these signal molecules, e.g., arachidonic acid, [Ca²⁺]_i and H₂O₂, rather one of them to activate TRPM2 channels under physiological conditions [30, 31, 33, 34].

TRPM2 channels localize not only in the β cell plasma membrane but also in lysosomes from which these channels mobilize Ca²⁺ to the cytosol compartment to participate in H₂O₂-induced apoptosis [33]. β Cells express antioxidant enzymes at relatively low levels and are vulnerable to oxidative damage [81]. Exposure of β cells to H₂O₂ gives rise to a significant increase in intracellular ADPR, which has been considered as the most potent and specific TRPM2 channel activator among all known endogenous TRPM2 channel-activating molecules [82]. ADPR activates TRPM2 channels by binding to the NUDT9-H domain of these channels to bring about both Ca²⁺ influx through the plasma membrane TRPM2 channels and Ca²⁺ release via the lysosomal TRPM2 channels [33, 83]. Indeed, both of these two ionic events mediate H₂O₂-induced β cell apoptosis, but the former is more important than the latter [33]. However, the latter alone suffices to trigger β cell apoptosis [33].

A puzzling ion flux for initiation of β cell action potentials

The commonly used paradigm of glucose-stimulated insulin secretion simply attributes initiation of β cell action potentials to depolarization induced by closure of the K_ATP channel-mediated K⁺ efflux. In fact, this closure alone hardly suffices to trigger β cell action potentials and insulin secretion [1, 2, 15]. On top of the closure of the K_ATP channel-mediated K⁺ efflux, a puzzling ion flux, which forms a depolarizing inward current, occurs across the β cell plasma membrane to initiate action potentials and insulin secretion [1, 2, 15]. It has been suggested that influx of both Na⁺ and Ca²⁺ is involved [15]. However, the ion species responsible for and the molecular device conducting such a depolarizing inward current remain in dispute. Current findings open up the following possibilities. Some researchers interpret the puzzling ion flux as a Cl⁻ efflux or a cation influx through TRP channels [40, 54, 84]. Others consider that the Na⁺/Ca²⁺ exchanger, cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and volume-regulated anion channel mediate this depolarizing inward current [1, 57, 85, 86]. The mouse β cell undergoes sub-threshold depolarization when bathed in 5 mM glucose after exposure to 10 mM glucose. Subsequently, removal of extracellular Na⁺ and Ca²⁺ leads to an obvious repolarization of the β cell plasma membrane [15]. This demonstrates that influx of both Na⁺ and Ca²⁺ apparently contributes to β cell depolarization when more than 90 % of K_ATP channel conductance is blocked by exposure to 5 mM glucose [15, 87, 88]. The depolarizing inward current resulting from this cation influx is characterized by a linear voltage dependence between −90 and −50 mV, a whole-cell slope conductance of 0.25 nS and an extrapolated reversal potential of about −20 mV [15]. It should be pointed out that thorough investigation is needed to determine ion identities and conducting molecules of the puzzling ion flux which is critical for initiating β cell action potentials and triggering insulin secretion.

Ca²⁺ mobilization from intracellular stores via inositol 1,4,5-trisphosphate receptor (IP₃R) ion channels and ryanodine receptor (RyR) ion channels

Ca²⁺ dynamics in the β cell depends not only on diverse Ca²⁺ fluxes across the plasma membrane but also on various Ca²⁺ shuttles among subcellular compartments. Ca²⁺ mobilization from intracellular stores is crucial for Ca²⁺ dynamics in the β cell [89]. The ligand-gated Ca²⁺ release channels, IP₃Rs and RyRs, mainly localize in the endoplasmic reticulum (ER) that stores large amounts of Ca²⁺ [62–65, 89]. Upon activation of IP₃Rs and RyRs by a variety of stimuli including neurotransmitters, hormones, metabolic fuels and Ca²⁺, stored Ca²⁺ rapidly releases into the cytosolic compartment through Ca²⁺-conducting pores of these ligand-gated channels resulting in complex dynamic changes in [Ca²⁺]_i [62–65, 89]. Glucose-induced [Ca²⁺]_i changes in the mouse islet manifest as fast oscillations with a period from several seconds to 1 min, slow oscillations with a period ranging from one to several minutes or mixed oscillations characterized by fast oscillations superimposed on slow oscillations [89–91]. These [Ca²⁺]_i changes result from corresponding alterations in the membrane potential of the β cell and trigger corresponding oscillatory insulin secretion [89–91]. Mouse β cells within an islet display neither compound electrical bursting, namely clusters of membrane potential oscillations separated by prolonged silent intervals, nor mixed [Ca²⁺]_i oscillations when the ER Ca²⁺ pool is depleted by the ER Ca²⁺ pump inhibitor thapsigargin or genetic ablation of the sarco/endoplasmic reticulum Ca²⁺ pump SERCA 3 [91]. The complex dynamic changes in [Ca²⁺]_i instruct not only exocytotic proteins to execute insulin exocytosis but also Ca²⁺-sensitive proteins, such as Ca²⁺-sensitive enzymes and Ca²⁺-sensitive transcription factors, to regulate corresponding molecular and cellular events [62–65, 89].

All three IP₃R subtypes (IP₃R1, IP₃R2 and IP₃R3) are present in the β cell ER membrane [62]. These IP₃-gated ion channels open their Ca²⁺-conducting pores in response to de novo activation of phospholipase C-linked G protein-coupled receptors, e.g., muscarinic M3 receptors and purinergic P2Y receptors [62]. Particularly, the most important physiological insulin secretagogue glucose efficiently elevates IP₃ levels in the β cell and consequently activates IP₃Rs to release Ca²⁺ from IP₃-sensitive stores into the cytoplasm [62]. This occurs because β cell PLC undergoes activation to produce IP₃ in response to glucose-induced depolarization, glucose-evoked Ca²⁺ influx or glucose-initiated autocrine stimulation of P2Y receptors by ATP coreleased with insulin [62]. Eventually, Ca²⁺ released from IP₃-sensitive stores participates in insulin granule trafficking and exocytosis as well as other Ca²⁺-dependent processes [62].

All three subtypes of RyRs, namely RyR1 RyR2 and RyR3, are embedded in the β cell ER membrane [64, 89]. In the physiological context, glucose-induced depolarization and Ca²⁺ influx as well as the glucose metabolism-derived molecules ATP, fructose 1,6-diphosphate, long-chain acyl CoA and cADPR activate these ryanodine-sensitive Ca²⁺ release channels [65, 89]. In response to these stimuli, RyRs undergo an extremely rapid conformational switch from an impermeable state to a highly permeable pore. The highly permeable pore allows Ca²⁺ in ryanodine-sensitive stores to rapidly release into the cytoplasm, where Ca²⁺ efflux from ryanodine-sensitive stores regulates insulin secretion and interacts with Ca²⁺-sensitive targets [65, 89].

ClC-3 Cl⁻ channel-mediated Cl⁻ entry into insulin granules

The insulin granule membrane mediates complex ion fluxes through several types of ion channels, e.g., K_ATP channels, ClC-3 Cl⁻ channels, TRP channels, IP₃R ion channels and RyR ion channels (Table 1) [30, 31, 66–72]. These ionic mechanisms play an important role in maturation, trafficking and priming of insulin granules [30, 31, 66–72]. The ClC-3 Cl⁻ channel-mediated Cl⁻ entry into insulin granules exemplifies the importance of ionic mechanisms occurring in the insulin granule membrane [69, 70]. Increase in the ATP/ADP ratio leads to an accelerated Cl⁻ entry through the ClC-3 Cl⁻ channel and a concomitantly elevated H⁺ uptake via the V-type H⁺-ATPase into the insulin granule [67]. Resultant intragranular acidification is not only prerequisite for conversion of proinsulin to insulin and formation of insulin crystals, but also activates the V0 domain of the V-type H⁺-ATPase, a pH sensor, which participates in priming and fusion of the secretory granule [92]. This is consistent with the fact that genetic ablation of ClC-3 Cl⁻ channels severely impairs intragranular acidification and insulin secretion evoked by depolarization or glucose stimulation [69, 70].

The K_ATP conductance determines the excitability of the β cell plasma membrane

At rest, the β cell plasma membrane is more permeable to K⁺ than to other ionic species [2]. The concentration of K⁺ is greater inside the β cell (150 mM) than outside (5 mM). Such a concentration gradient drives a net diffusion of K⁺ across the plasma membrane out of the β cell. The K⁺ conductance sets the resting membrane potential of the β cell to near the K⁺ equilibrium potential (−75 mV) [2]. K⁺ channels embedded in the plasma membrane serve as molecular substrates for K⁺ conductance [93, 94]. The body is equipped with a variety of K⁺ channels due to the diversity of K⁺ channel genes [93, 94]. Virtually, all cells in the body express K⁺ channels [93, 94]. Generally speaking, all types of K⁺ channels are involved in stabilization of the membrane potential acting as a brake on electrical excitability. Open K⁺ channels drive the membrane potential closer to the K⁺ equilibrium potential and further away from the firing threshold of the action potential. Some types of K⁺ channels open in response to depolarization and ligand binding, but are otherwise closed [93, 94]. In contrast, other K⁺ channels are open at rest to sustain the resting membrane potential [93, 94].

Different types of cells employ distinct classes of K⁺ channels to set the resting membrane potential [93, 94]. The β cell alters its membrane potential below the action potential threshold by opening or closing K_ATP channels and thereby determining the excitability of the β cell plasma membrane (Fig. 1) [2, 13, 23, 95]. Noteworthy is that the β cell does not fire an action potential even though more than 90 % of the K_ATP channels are closed. Further closure of the remaining K_ATP channels (less than 10 %) leads to depolarization of the β cell plasma membrane up to the action potential threshold and action potential firing [15, 96]. β cell K_ATP channel activity exponentially decreases with increasing glucose concentration. Incubation with 2–3 mM glucose, commonly used to maintain basal insulin release in vitro, already inhibits 50 % of the K_ATP currents in the β cell, but still maintains a stable resting membrane potential and thus low level of β cell excitability. When glucose is elevated to a fasting blood glucose level of 5 mM, more than 90 % decrease in K_ATP channel activity, sub-threshold depolarization and corresponding increase in β cell excitability occur. Exposure to glucose concentrations above 7 mM completely blocks β cell K_ATP channels leading to supra-threshold depolarization and action potential firing [15, 87, 88]. Figure 1 shows that exposure to a stimulatory glucose concentration (16.7 mM) gradually closes K_ATP channels resulting in a corresponding depolarization and an equivalent decrease in the K_ATP conductance (gK_ATP) (Fig. 1). Consequently, β cell excitability gradually increases (Fig. 1).

Fig. 1 — Characteristics of β cell responses to glucose stimulation. a Membrane potential changes in a mouse pancreatic β cell induced by a step increase in glucose concentration from 2.8 to 16.7 mM. K_ATP channels open at a basal glucose level (2.8 mM) and maintain low levels of β cell excitability. K_ATP channels gradually close, as manifested by a corresponding depolarization and an equivalent decrease in the K_ATP conductance (gK_ATP), following exposure to a stimulatory glucose concentration (16.7 mM). Ca_V1 channels open as soon as the β cell plasma membrane is depolarized to the firing threshold of action potentials. The Ca_V1 channel-mediated Ca²⁺ entry results in a rapid, further depolarization of the β cell plasma membrane causing the upstroke or depolarization phase of the action potential reflected by a rapid increase in the Ca_V1 conductance (gCa_V1). The delayed rectifier K⁺ channel K_V2.1 becomes activated to mediate a K⁺ efflux when the action potential reaches its peak. The K_V2.1 channel-mediated efflux quickly repolarizes the β cell plasma membrane leading to the downstroke or repolarization phase of the action potential, which acts as a brake for insulin secretion due to shutting down the Ca_V channel-mediated Ca²⁺ entry. b Comparison of K_ATP channel activity, electrical activity and insulin secretion induced by different concentrations of glucose between human and mouse β cells [13, 15, 87, 88, 96, 239–242]

Structure and properties of β cell K_ATP channels

The β cell K_ATP channel mediates the resting K⁺ conductance that is effectively blocked by intracellular ATP and regulated by numerous physiological stimuli and pharmacological compounds [2, 13, 23, 95]. Obviously, alteration in the K⁺ conductance through β cell K_ATP channels shifts the membrane potential leading to changes in the excitability of the β cell plasma membrane. This makes β cells rely on K_ATP channels to initiate and end the β cell-unique function in terms of glucose-stimulated insulin secretion [2, 13, 23, 95]. Therefore, it is of importance to understand the structural bases for β cell K_ATP channel conductivity and β cell K_ATP channel regulation as well as underlying mechanisms.

The K_ATP channel consists of potassium inward rectifier 6 (Kir6.x) and sulfonylurea receptor (SURx) subunits (Fig. 2) [3–5]. The former is a pore-forming subunit, being a member of the inward rectifier K⁺ channel family. The latter belongs to the ATP-binding cassette protein family and acts as a regulatory subunit [3–5]. Mammalian K_ATP channels are encoded by two Kir6.x genes, Kir6.1 (KCNJ8) and Kir6.2 (KCNJ11), and two SURx genes, SUR1 (ABCC8) and SUR2 (ABCC9). Both the SUR1 and SUR2 can be alternatively spliced into multiple isoforms. The alternatively splicing isoforms of SUR1 and SUR2 genes selectively express in different cell types with either Kir6.1 or Kir6.2 to form cell-type specific K_ATP channels [3–5].

The β cell K_ATP channel is composed of the Kir6.2 and SUR1 subunits (Fig. 2) [3–5]. The small Kir6.2 subunit contains two transmembrane helices (M1 and M2) as well as intracellular N- and C-terminal tails. The large SUR1 subunit comprises a five-helix transmembrane domain (TMD0), two six-helix transmembrane domains (TMD1 and TMD2) and two nucleotide-binding folds (NBF1 and NBF2) with extracellular N- and intracellular C-terminal ends [3–5]. Four Kir6.2 and four SUR1 subunits physically associate with each other to assemble into a compact structure (~18 nm in cross-section and ~13 nm in height) [97]. Kir6.2 subunits stand in the middle of the structure and their M1 and M2 helices linked by an extracellular loop form a K⁺-conducting pore. The cytoplasmic regions of each Kir6.2 subunit constitute binding sites for ATP and phosphatidylinositol 4,5-bisphosphate (PIP₂) to stabilize closed and open states of the channel, respectively [5, 97]. It has been suggested that the ATP-binding site is situated 2 nm below the membrane. The ATP-binding site is juxtaposed and overlaps with the PIP₂-binding site. SUR1 subunits are symmetrically grouped around Kir6.2 subunits to act as regulatory subunits. SUR1 subunit NBFs provide MgATP and MgADP binding sites [5, 97].

Electrophysiological properties of β cell K_ATP channels have been thoroughly characterized [2, 13, 23, 98]. These channels in inside-out patches exhibit unitary conductances of 50–65 pS in a symmetrical 140 mM K⁺ gradient and 20–30 pS in the physiological K⁺ gradient ([K⁺]_o/[K⁺]_i of 5/150 mM) in the absence of internal blocking cations [2, 98–102]. The K_ATP channel unitary conductance measured in cell-attached patches with pipette containing 5 mM K⁺ drops to 13–15 pS due to the presence of intracellular blocking ions [2, 103, 104]. The current–voltage relationship for single K_ATP channels in cell-attached patches shows a pronounced inward rectification as manifested by a small increase in currents at potentials above +20 mV [2, 101]. Whole-cell K_ATP currents range between 100 and 200 pA induced by +10 mV excursions from a holding potential of −70 mV in the physiological K⁺ gradient after washout of cytoplasmic ATP [105, 106]. Under the same experimental conditions, the maximum whole-cell K_ATP conductance falls within the range between 10 and 20 nS and the K_ATP channel unitary conductance is about 20 pS [2, 99, 105, 106]. The density of functional K_ATP channels in the β cell can be estimated according to the equation G = NPγ where G is the whole-cell conductance, N is the number of K_ATP channels in the β cell, P is the open probability of the channel and γ is the single-channel conductance. An estimate of 500–1,000 functional K_ATP channels per cell is obtained if P is taken as 1. However, this value is underestimated since that P is considerably less than 1. The open probability of β cell K_ATP channels is expected to lie between 0.1 and 0.4 and can maximally reach up to 0.8 [107]. Therefore, the β cell is equipped with more than the above-estimated 500–1,000 functional K_ATP channels. It is noteworthy that the input resistance of the resting human β cell is considerably higher than that of the resting mouse β cell. This is clearly manifested in cell input resistance measurements where the resting membrane conductance is 60 pS/pF in the human β cell and 700 pS/pF in the mouse β cell [13, 96]. This demonstrates that the fraction of open K_ATP channels in the resting human β cell are significantly less than those in the resting mouse β cell and may at least partly explain why lower glucose concentrations are required for initiation of action potential firing and insulin secretion in human β cells compared to mouse β cells [13].

Regulation of β cell K_ATP channels

To fine-tune the excitability of the β cell plasma membrane and consequently control β cell function and in particular glucose-stimulated insulin secretion, the β cell K_ATP channel is subjected to regulation by a variety of physiological stimuli and pharmacological compounds, some of which are discussed below.

Cytoplasmic nucleotides

The K_ATP channel is defined in terms of ATP inhibition of its conductivity. Such an ATP inhibition endows K_ATP channels with the ability to serve as molecular sensors of β cell energy metabolism [5]. The β cell efficiently takes up glucose through the high capacity, low affinity glucose transporter-2. Subsequently, glucose undergoes metabolism in both glycolysis and the tricarboxylic acid cycle to produce ATP. ATP binds to ATP-binding sites in the Kir6.2 subunits causing inhibition of K_ATP channels, reduction in the ATP-sensitive K⁺ conductance and elevation in the excitability of the β cell plasma membrane (Figs. 1, 2, 5) [2, 5, 8, 14]. The ATP binding generates the energetic push to shut the ligand-operated gate of the K_ATP channel. Apparently, there are four ATP binding sites per K⁺ conducting pore made up of four Kir6.2 subunits. However, occupation of one ATP binding site in a Kir6.2 subunit is sufficient to close the channel [5]. The precise underlying mechanism remains to be clarified. K_ATP channels in different cell types display distinct ATP sensitivities [3, 4]. In inside-out patches, the half-maximal inhibitory concentration for ATP on β cell K_ATP channels is 5–15 μM [3]. ATP at 1 mM can completely ablate the K⁺ conductance through β cell K_ATP channels in isolated membrane patches [3, 108]. ATP binding to Kir6.2 subunits and inhibition of their conductivity are Mg-independent and do not require ATP hydrolysis [3, 5, 108].

Fig. 5 — A scheme depicting functions and regulatory mechanisms of ion channels and cytosolic free Ca²⁺ in β cells. The β cell is equipped with three major types of ion channels, K_ATP, Ca_V1 and K_V2.1. These channel-mediated ion fluxes establish the resting membrane potential, the depolarization and repolarization phases of the action potential, respectively, constituting complex electrical signaling systems. These electrical signaling systems are coupled to the versatile signaling molecule Ca²⁺ that participates in the regulation of all known molecular and cellular events, such as exocytosis, endocytosis, protein phosphorylation, gene expression, metabolism, differentiation, growth and even cell death. β Cell K_ATP, Ca_V1 and K_V2.1 are regulated by a diverse range of mechanisms to generate distinct electrical signals under different physiological and pathological conditions. Ca ²⁺ */CaM* Ca²⁺/calmodulin, *CAC* citric acid cycle, EV endocytotic vesicles, G GTP-binding protein, *GLUT* glucose transporter, *GMS* glucose metabolism-derived signal, *GPCR* GTP-binding protein-coupled receptor, IG insulin-containing granule, *InsP* ₃ R InsP₃ receptor, P phosphoryl group, *PIP* ₂ phosphatidylinositol 4,5-bisphosphate, *PLC* phospholipase C, *PPase* protein phosphatase, *RyR* ryanodine receptor, *TKR* tyrosine kinase receptor, ψ depolarization

The negatively charged ATP binds Mg²⁺ with a greater affinity than other cations and thus exists in the cell mostly in a complex with Mg²⁺ [109, 110]. As stated above, intracellular MgATP predominantly inhibits K_ATP channels by binding to Kir6.2 subunits, but indeed has a small stimulatory effect on these channels via interaction with SUR1 subunits. Both MgATP and MgADP interact with NBFs of the SUR1 subunits resulting in activation of K_ATP channels, elevation in the ATP-sensitive K⁺ conductance and reduction in the excitability of the β cell plasma membrane (Figs. 1, 2). Available data indicate that MgATP does not activate the channel directly and must be hydrolyzed to MgADP that makes the channel open by binding to NBFs of the SUR1 subunit [5, 108]. It is believed that there are two ATP binding pockets, namely sites 1 and 2. Site 1 is formed by the Walker A and Walker B motifs of NBF1 plus the linker motif of NBF2, whereas site 2 is composed of the Walker A and Walker B motifs of NBF2 plus the linker motif of NBF1 (Fig. 2). The latter hydrolyzes bound ATP. In intact cells, the stimulatory effect of Mg-nucleotides decreases the sensitivity to ATP inhibition [5, 108]. This cannot fully explain why intact β cells containing 1–5 mM ATP at rest exhibit significant K_ATP channel activity and further close K_ATP channels in response to glucose stimulation. Intracellular free MgADP concentration (about 50 µM) is namely too low to antagonize inhibition of K_ATP channels by 1–5 mM ATP [108, 111]. Consequently, other endogenous K_ATP channel openers such as phosphatidylinositols and long-chain acyl-CoA ester may also be considered in this context [108, 111].

Phosphatidylinositols

The lipid bilayer of the cell membrane not only physically hosts K_ATP channels, but also functionally interacts with these channels (Fig. 5). Phosphatidylinositol 4-phosphate, PIP₂ and phosphatidylinositol 3,4,5-trisphosphate play important roles in stabilizing open states of K_ATP channels although these phosphatidylinositols just constitute a minor phospholipid component at the cytosolic side of the cell membranes [4, 5]. Decreases and increases of phosphatidylinositol 4-phosphate, PIP₂ or phosphatidylinositol 3,4,5-trisphosphate in the cell membrane significantly inhibit and activate K_ATP channel activity, respectively, by altering the open probability of the channel (Fig. 5) [4, 5, 112, 113]. Intracellular application of PIP₂ potently augments the whole-cell K_ATP conductance. Diminution in the plasma membrane PIP₂ by P2Y receptor-mediated activation of phospholipase C markedly decreases whole-cell K_ATP currents. Both heterologously expressed Kir6.2/SUR1 and β cell K_ATP channels in inside-out patches display a gradual run-down that can be effectively prevented by addition of PIP₂ [112, 113]. Molecular and structural analyses indicate that the Kir6.2 subunit possesses a PIP₂ binding site adjacent to the ligand-operated gate of the K_ATP channel. PIP₂ occupation of this binding site causes the energetic pull to open the gate and stabilize the channel in an active conformation [5, 97]. Interestingly, PIP₂ also potently counteracts the inhibitory effect of ATP on the K_ATP channel causing a drastic decrease in the ATP sensitivity of the channel [5, 112, 113]. This negative heterotropic interaction between PIP₂ and ATP is believed to be due to the juxtaposition and partial overlap of PIP₂ binding sites with ATP-binding sites in the Kir6.2 subunit [5]. This adds another explanation to the longstanding dilemma that K_ATP channels do not close in intact β cells containing 1–5 mM ATP at rest, but close following glucose stimulation.

Actin cytoskeletal network

In addition to phosphatidylinositols in the inner leaflet of the plasma membrane, the actin cytoskeletal network is also important in sustaining the K_ATP channel in an active form (Fig. 5) [114]. Actin depolymerizers significantly facilitate the run-down of K_ATP channel in inside-out patches, whereas actin polymerizers fully impede it. F-actins plus MgATP can evidently restore the activity of run-down K_ATP channels, but G-actins together with MgATP fail to do so [114].

G protein-coupled receptors

Activation of G protein-coupled receptors mediates autocrine feedback and parasympathetic input to β cells to facilitate glucose-stimulated insulin secretion. This occurs, at least in part, due to reduced K_ATP channel activity resulting from decreased PIP₂ and increased [Ca²⁺]_i upon activation of P2Y receptors and muscarinic receptors in the β cell plasma membrane [112, 113, 115–117]. ATP coreleased with insulin serves as an endogenous ligand to activate both P2X and P2Y receptors. The P2Y receptor downstream target K_ATP channel undergoes closure in response to activation of this purinergic receptor (see “Phosphatidylinositols” for details) [112, 113, 116, 117]. Activation of muscarinic acetylcholine receptors significantly reduces K_ATP currents recorded in the rat islet β cell using a perforated-patch whole-cell recording [115]. As a result of the inhibition of K_ATP channels by activation of muscarinic acetylcholine receptors, the β cell becomes strongly depolarized to fire action potentials [115]. The effect is effectively ablated by inhibition of phospholipase C or chelation of intracellular Ca²⁺. Exposure of K_ATP channels in inside-out patches to 10 μM Ca²⁺ significantly reduces channel activity in the presence of ATP [115]. Ca²⁺ at higher concentrations effectively induces K_ATP channel rundown in the absence of ATP [114]. Comparatively speaking, the increased [Ca²⁺]_i appears to be more important than the decreased PIP₂ in down-regulation of K_ATP channel activity by activation of muscarinic acetylcholine receptors. This is because acetylcholine can no longer inhibit β cell K_ATP channel activity when the increased [Ca²⁺]_i is prevented without influencing activation of PLC [115].

Protein kinase A

Protein phosphorylation is also a regulatory mechanism for β cell K_ATP channel conductivity and density (Fig. 5). Protein kinase A (PKA) phosphorylation of K_ATP channels and its functional consequences have been firmly verified [118]. At least, two PKA phosphorylation sites (threonine 224 and serine 372) have been verified in the Kir6.2 subunit. PKA catalytic subunits or activation of G protein-coupled receptors can effectively phosphorylate these two residues resulting in a significant increase in channel open probability [118]. The PKA phosphorylation site has also been identified in the SUR1 subunit [118]. The basal PKA activity is sufficient for phosphorylation of the SUR1 subunit at its serine 1571. Such a phosphorylation decreases burst duration, interburst interval and open probability of the K_ATP channel, but increases the number of the channel in the plasma membrane [118]. Indeed, the above data were obtained in heterologous expression systems and insulin-secreting MIN6 cells subjected to in vitro manipulation of PKA or G protein-coupled receptors. Nevertheless, physiological significances of these in vitro data can be inferred as follows. At basal glucose concentration, autonomic innervation and paracrine feedback loops likely suffice to activate β cell Gs protein-coupled receptors and thereby PKA phosphorylation of K_ATP channels. Such a K_ATP channel phosphorylation serves to preserve adequate K_ATP channel activity to set up the resting membrane potential of the β cell. As aforementioned, ATP concentrations (1–5 mM) in resting β cells could fully block K_ATP channels if there was no antagonism against such a blocking effect. In addition to stimulation by phosphatidylinositols and MgADP, Gs protein-coupled receptor-dependent PKA phosphorylation of β cell K_ATP channels is likely to be another mechanism counteracting inhibition of K_ATP channels by high concentration of ATP in resting β cells.

Interestingly, intracellular K_ATP channels have been visualized in chromogranin-positive/insulin-negative dense-core granules [73]. Glucose stimulation can recruit these K_ATP channels to the β cell plasma membrane via these novel secretory granules in a Ca²⁺- and PKA-dependent manner [73]. It should be pointed out that the increase in PKA activity concomitant with glucose stimulation promotes the recruitment of K_ATP channels to the β cell plasma membrane, but does not alter K_ATP channel activity [73]. This suggests that maximal PKA phosphorylation of K_ATP channels already occurs at basal glucose concentrations due to activation of Gs protein-coupled receptors by neurotransmitters such as adrenaline released from autonomic nerve terminals and hormones e.g., glucagon exocytosed from α cells. Therefore, the glucose-induced activation of PKA promotes secretory granule trafficking and exocytosis but cannot further phosphorylate K_ATP channels reducing β cell excitability during glucose stimulation. The recruited channels may act as a constituent of the exocytotic machinery to mediate insulin release independent of their electrical function since SUR1 subunits play an essential role in cAMP-dependent/PKA-independent insulin secretion by interacting with cAMP-GEFII, Piccolo, RIM2, Rab3, and Ca_V1.2 subunits [119]. Taken together, PKA phosphorylation not only regulates K_ATP channel conductivity, but also promotes its trafficking to the cell surface [4, 73].

Protein kinase C

Protein kinase C (PKC) phosphorylation regulates both the conductivity and the density of K_ATP channels in the plasma membrane [120, 121]. Brief activation of PKC results in phosphorylation of threonine 180 of the Kir6.2 subunit [121]. This phosphorylation occurs at Kir6.2Δ26 subunits alone or Kir6.2 associated with SUR1 or SUR2A subunits heterologously expressed in tsA201 cells [121]. It decreases K_ATP channel activity at lower ATP concentrations, but increases K_ATP channel activity at higher ATP concentrations [121]. The physiological relevance of the data remains elusive. Prolonged activation of PKC down-regulates the number of Kir6.2/SUR1 channels heterologously expressed in Xenopus oocytes or COS-7 cells [120]. Interestingly, this down-regulation still occurs when PKC consensus sites in Kir6.2 are mutated, but disappears when the dileucine motif is depleted from Kir6.2 [120]. This is because the dileucine motif targets its host proteins in the plasma membrane to endosomes by interacting with the AP2 complex, a critical regulator of dynamin-dependent endocytosis. Such endocytosis is vitally controlled by PKC phosphorylation [120]. Apparently, dynamin-dependent endocytosis rather than PKC phosphorylation of Kir6.2 subunits per se mediates the down-regulation of Kir6.2/SUR1 channels [120]. It would be interesting to clarify if down-regulation of β cell K_ATP channel density occurs in a physiological context where PKC is activated.

Pharmacological blockers

Owing to the importance of the β cell K_ATP channel in glucose-stimulated insulin secretion, this channel has been identified as and proven to be an important therapeutic target in pharmacological treatment of type 2 diabetes and insulin hypersecretion associated with insulinoma and familial persistent hyperinsulinemic hypoglycemia of infancy [3, 4]. Both K_ATP channel blockers and openers have been developed and used to treat these diseases for decades. There are two classes of K_ATP channel blockers designed for therapeutic use, sulfonylureas and glinides [3, 4]. Although they are structurally dissimilar, they share similar pharmacological actions depending on equivalent mechanisms. Sulfonylureas and glinides function as insulin secretagogues by closing β cell K_ATP channels and secondarily opening β cell Ca_V channels. The following discusses β cell K_ATP channel blockers exemplified by sulphonylureas. The first generation of oral hypoglycemic sulfonylurea agents such as tolbutamide was derived from antibacterial sulfonamides as a consequence of the observations made during World War II, namely, that patients treated with these antibacterials often developed hypoglycemia. However, they are not satisfactorily potent. Therefore, pharmaceutists developed the second generation of sulfonylureas represented by glibenclamide with high potency. Glibenclamide binds to human SUR1 subunits expressed in COS-7 cells 40,000 times more strongly than tolbutamide [122]. The binding affinity and inhibition potency of glibenclamide are 20,000 times and 50,000 times higher than those of tolbutamide, respectively [122]. Glibenclamide is not only a high-potency antidiabetic drug, but also a useful research tool. It was this reagent that fished out its binding partner sulfonylurea receptor for the first time. The sulfonylurea binding site is localized in the intracellular loop between TMD0 and TMD1 of SURx subunits [3, 4]. A detailed picture of the binding site remains to be elucidated.

Pharmacological openers

K_ATP channel openers are a diverse group of drugs exhibiting a great chemical diversity and pharmacological selectivity. They increase cell membrane permeability to K⁺ resulting in cell membrane hyperpolarization and consequent inhibition of action potential generation. The well-characterized K_ATP channel opener diazoxide is commonly used to suppress excessive insulin secretion in patients with insulinoma and familial persistent hyperinsulinemic hypoglycemia of infancy by activating β cell K_ATP channels [3, 4]. The clinical effect of diazoxide depends on selective binding of this drug to the SUR1 subunit. This subunit carries a diazoxide binding site, but its precise location is still uncertain. Domain exchange between diazoxide-sensitive SUR1 and diazoxide-insensitive SUR2A subunits indicates that the TMD1 plus NBF1 from the SUR1 subunit is responsible for diazoxide binding [3, 4].

Ca²⁺ influx through β cell Ca_V channels mainly controls insulin secretion

Like other ion channel-mediated ion fluxes, Ca²⁺ influx through Ca_V channels alters the cell membrane potential. It contributes to the upstroke of the action potential in certain types of excitable cells. The pancreatic β cell is one of the excitable cells employing Ca_V channels in the generation of action potentials. During action potentials, the Ca_V channel-mediated Ca²⁺ influx into the β cell mainly controls insulin secretion although it is also involved in the regulation of other β cell functions [7, 8, 14, 123, 124]. The major β cell Ca_V channel Ca_V1 opens immediately when the β cell plasma membrane is depolarized to the firing threshold of action potentials following stimulation with high glucose (Fig. 1). Ca²⁺ entry through Ca_V1 channels leads to a rapid further depolarization of the β cell plasma membrane, namely the upstroke or depolarization phase of the action potential manifested as a rapid increase in the Ca_V1 conductance (gCa_V1) (Fig. 1).

Structure, classification and properties of β cell Ca_V channels

The Ca_V channel is a multiple protein complex containing the Ca_Vα₁, Ca_Vα₂/δ, Ca_Vβ and Ca_Vγ subunits (Fig. 3) [8, 125–130]. The Ca_Vα₁ subunit as the principal element of the Ca_V channel complex constitutes a pore structure to conduct Ca²⁺ in response to membrane depolarization (Fig. 3). The Ca_Vα₂/δ, Ca_Vβ and Ca_Vγ subunit do not directly contribute to building up the Ca²⁺-conducting pore, but are intimately associated with the Ca_Vα₁ subunit to regulate its conductivity and trafficking. Therefore, they are referred to as auxiliary subunits (Fig. 3) [8, 125, 126]. Ten Ca_Vα₁ subunits, Ca_V1.1, Ca_V1.2, Ca_V1.3, Ca_V1.4, Ca_V2.1, Ca_V2.2, Ca_V2.3, Ca_V3.1, Ca_V3.2 and Ca_V3.3, have been characterized (Fig. 3). They associate with certain auxiliary subunits to mediate L-, P/Q-, N-, R- and T-type Ca_V currents, respectively (Fig. 3) [8, 125]. In general, all these types of Ca_V currents are recorded in β cells. They are conducted by Ca_V1.2, Ca_V1.3, Ca_V2.1, Ca_V2.2, Ca_V2.3, Ca_V3.1 and Ca_V3.2 subunits in combination with certain auxiliary subunits [7, 8, 11]. However, obvious interspecies differences in expression of Ca_V currents have been revealed in the β cell [7, 8]. For example, Ca_V3 currents are clearly visualized in the human and rat β cell, but not in the mouse β cell. Ca_V2.3 channels are not present in the human β cell [7, 8, 11, 13, 131].

The Ca_Vα₁ subunit possesses four homologous domains, each consisting of six transmembrane segments (S1 to S6) and a membrane-associated pore loop (P-loop) between the S5 and S6 segments, three intracellular linkers, and N- and C-termini. The four homologous domains are structured into a Ca²⁺-conducting pore equipped with activation and inactivation gates and controlled by voltage sensors. Four pairs of the S5 and S6 segments along with the P-loops line the Ca²⁺-conducting pore. The Ca²⁺ selectivity of the pore relies on four glutamic acid residues situated in the four P-loops of high-voltage activated Ca²⁺ channels or two glutamic and two aspartic acid residues localized in the corresponding positions of low voltage activated Ca²⁺ channels. The S4 segments function as the principal voltage sensors in Ca_V channels. The depolarization-evoked movement of the voltage sensors results in the conformational change and/or physical reposition of activation and inactivation gates to open the channel and to reduce channel permeability, respectively [7, 8, 93, 125].

Three-dimensional structures of Ca_V channels have been partially depicted by electron microscopy and X-ray crystallography. Single-particle electron microscopy shows that Ca_V1.2 channels purified from bovine heart and expressed in β cells are complexed to a stable dimer consisting of two arch-shaped monomers [7, 8, 132]. This complex is composed of Ca_Vα₁, α₂, β and δ subunits and is roughly toroidal in shape (19 nm in height, 19 nm in width and 14.5 nm in depth). The two arches contact at the extracellular and intracellular sides of the complex. The top end of the complex is termed the nose, whereas the bottom end of the complex is occupied by Ca_Vβ subunits. There are two finger-like protrusions, i.e., finger domains, extending from the two arches that curl around on each side to the front and back side of the toroidal complex. The nose and finger domains are mainly formed by Ca_Vα₂ subunits. The two arches and two finger domains enclose a central aqueous chamber with a ~5 nm × 3 nm × 4 nm volume (height × width × depth) [132]. Recently, X-ray crystallography in combination with patch-clamp analysis has clearly dissected the structure–function relationships of the Ca²⁺ selectivity filter of Ca_V channels [133]. This filter is made of two high-affinity and one low affinity Ca²⁺-binding sites named Site 1 (high-affinity), Site 2 (high-affinity) and Site 3 (low affinity) from the extracellular to the intracellular side. Hydrated Ca²⁺ interacts with Sites 1 and 2 followed by Site 3 when passing through the filter. The interaction between these Ca²⁺-binding sites via a knock-off mechanism drives transient changes of the selectivity filter between two states with either one hydrated Ca²⁺ bound at site 2 or two hydrated Ca²⁺ ions bound at sites 1 and 3. The high-affinity binding of Ca²⁺ to Sites 1 and 2 prevents permeation of Na⁺ and other monovalent cations and high extracellular Ca²⁺ enables its inward movement by rapidly binding to Site 1. The ionic repulsion between Ca²⁺ ions bound at these sites cooperates with the stepwise change in Ca²⁺ binding affinity of these sites to guarantee rapid conductance despite of the intrinsic high affinity for Ca²⁺ binding [133]. The complex of the α₁-interaction domain (AID) in the Ca_Vα₁ subunit with the Ca_Vβ subunit has been visualized at the atomic level [134, 135]. The Ca_Vβ subunit core is structured by a SH3 domain and a GK domain. The latter holds a hydrophobic groove which binds the α-helical AID. This provides the Ca_Vβ subunit with the ability to directly modulate the movement of the IS6 segment in the Ca_Vα₁ subunit influencing channel pore gating, since the AID helix N-terminus is very close to the pore-lining segment IS6 [134, 135].

Combination of conventional whole-cell patch-clamp analysis and pharmacological manipulation reveals that Ca_V1, Ca_V2.1 and Ca_V2.3 channels mediate 50, 10–15 and 25 % of the integrated whole-cell Ca_V current, respectively, in the mouse β cell [131, 136]. The mouse β cell Ca_V current activates at around −50 mV, reaches peak amplitude (about 50 pA) between −10 and +10 mV, inactivates slowly and reverses at about +50 mV [7, 8, 137]. This reversal potential deviates somewhat from the Ca²⁺ equilibrium potential due to the presence of other ions [7, 8, 137]. The mouse β cell Ca_V current at −10 mV activates with a time constant of 1.28 ± 0.08 ms [137]. The same experimental approach has also been used to characterize whole-cell Ca_V currents in the human β cell [11, 13, 131]. The human β cell Ca_V current appears at potentials positive to −60 mV and reaches its peak density of 14 pA/pF at 0 mV, undergoes obvious inactivation and reverses at about +50 mV [11, 13, 131]. It activates with a time constant of 0.41 ± 0.02 ms at 0 mV and biphasically inactivates with a fast time constant of 6.8 ± 0.4 ms and a slow time constant of 65 ± 15 ms [11]. The human β cell engages Ca_V1, Ca_V2.1 and Ca_V3.2 channels to mediate Ca_V currents. Ca_V1 and Ca_V2.1 channels make an equal contribution (40–45 %) to the integrated whole-cell Ca_V current, whereas Ca_V3.2 channels only marginally contribute to a transient component (6 %) of the integrated whole-cell Ca_V current [11, 13, 131]. Ca_V3.2 channels activate at potentials positive to −60 mV, conduct maximal inward Ca²⁺ currents at −30 mV and undergo voltage-dependent inactivation with a half-maximal voltage of −65 mV and a time constant of about 40 ms at potentials positive to −50 mV [11, 13, 131]. Ca_V1 currents become detectable at −40 mV and peak between −20 and −10 mV, whereas Ca_V2.1 channels became active at −20 mV and conduct a maximal inward Ca²⁺ currents at 0 mV [11, 13, 131]. Both Ca_V1 and Ca_V2.1 currents activate quickly and can peak within less than 5 ms [11, 13, 131]. Noteworthy is that Ca_V1 channels rather than Ca_V2.1 channels inactivate in a Ca²⁺-dependent way with a time constant of 40 ms at 0 mV [11, 13, 131].

Regulation of insulin secretion by Ca²⁺ influx through β cell Ca_V channels

It is likely that all types of β cell Ca_V channels participate in the regulation of insulin secretion [7, 8, 14]. Ca²⁺ influx through β cell Ca_V1 channels plays a predominant role in control of insulin secretion over that mediated by other types of β cell Ca_V channels. It is responsible for 60–80 % of glucose-induced insulin secretion from mouse and rat islets and regulates both phases of insulin secretion, but more prominently the first phase [8, 136, 138]. Ca²⁺ entry through Ca_V2.1 channels is second only to that through Ca_V1 channels in the control of glucose-stimulated insulin secretion in rodents [8]. Ca_V2.1 channels are the most important in regulation of glucose-stimulated insulin secretion in human β cells [11, 131]. It is still a matter of debate whether the Ca_V2.2 channel-mediated Ca²⁺ entry participates in the regulation of insulin secretion [8]. It has been shown that the Ca_V2.2 channel blocker ω-CTX GVIA produces the null effect on glucose-induced insulin secretion in human islets. On the contrary, this blocker has been observed to inhibit second phase glucose-induced insulin secretion from rat islets [8]. Both pharmacological blockade of the Ca_V2.3 channel and genetic ablation of the Ca_V2.3 subunit firmly confirm the important role of Ca_V2.3 channels in insulin secretion [14, 139]. Detailed analysis reveals that Ca²⁺ influx through Ca_V2.3 channels selectively contributes to the regulation of second phase glucose-stimulated insulin secretion without affecting the first phase [14, 139]. It is tempting to speculate that β cell Ca_V1 channels self-organize into triplets and physically associate with syntaxin 1 and SNAP-25 to form local high [Ca²⁺]_i-driven exocytotic sites, whereas Ca_V2 channel-mediated Ca²⁺ influx contributes to global [Ca²⁺]_i to recruit insulin granules to exocytotic sites [131, 140]. The differential localization and organization of Ca_V1 and Ca_V2 channels provide a reasonable explanation for selective regulation of first and second phase glucose-stimulated insulin secretion by Ca_V1 and Ca_V2 channels [131, 140].

The regulation of insulin secretion by the Ca_V3 channel-mediated Ca²⁺ entry has been demonstrated in INS-1 cells [8, 141]. It is, however, uncertain that it occurs also in primary β cells although the non-selective Ca_V channel antagonist flunarizine, inhibiting both Ca_V1 and Ca_V3 channels, attenuates glucose- as well as K⁺-induced insulin secretion from perifused rat islets [8, 142].

Regulation of β cell Ca_V channels

Although the membrane potential determines the extent to which β cell Ca_V channels open, the conductivity and density of these channels are regulated by a diverse range of mechanisms that alter β cell Ca_V channel function and in particular Ca²⁺-dependent insulin secretion (Fig. 5) [7, 8, 14]. Generally speaking, these regulatory mechanisms coordinate with each other to drive adequate insulin secretion in the context of physiology [7, 8]. One or some of them predominate over others in a particular scenario [7, 8]. For example, parasympathetic activity and blood glucagon-like peptide-1 levels increase during food ingestion [7, 8]. They activate muscarinic receptors and glucagon-like peptide-1 receptors, respectively. This synchronous activation upregulates β cell Ca_V channel activity through stimulation of PKA and PKC and facilitates glucose-stimulated insulin secretion [7, 8]. Obviously, the glucagon-like peptide-1 receptor- and muscarinic receptor-mediated up-regulation of β cell Ca_V channel activity is more important than other mechanisms during food ingestion. We discuss different types of important regulatory mechanisms of β cell Ca_V channels below.

Protein kinases

β cell Ca_V channels carry multiple protein phosphorylation sites. Therefore, their Ca²⁺ conductivities are regulated by protein kinases and protein phosphatases (Fig. 5) [8]. It is clear that activation of PKA enhances the activity of β cell Ca_V1 channels [8, 143–146]. However, activation of PKC produces complicated effects on β cell Ca_V channels [147–149]. For example, depletion of PKC down-regulates L-, P/Q- and non-N-type Ca_V currents to the same extent in insulin-secreting RINm5F cells. Acute activation of PKC marginally increases Ca_V currents only in a small proportion of RINm5F cells (24 %). The effect occurs predominantly to Ca_V1 channels [8]. The PKG activator cGMP increases Ca²⁺ influx through Ca_V1 channels in rat pancreatic β cells [150]. However, it is uncertain that this effect results from activation of PKG since cGMP can produce a direct effect on Ca_V channels bypassing PKG [8, 151]. Likewise, it is not clear if calcium/calmodulin-dependent kinase II (CaMKII) regulates β cell Ca_V channel activity. Indeed, the non-specific CaMKII inhibitors KN-62 and KN-93 inhibit Ca²⁺ influx through β cell Ca_V channels [152, 153]. However, they may bypass CaMKII to directly act on β cell Ca_V channels [8]. Inhibition of protein phosphatases with okadaic acid just produces a smaller increase under basal conditions, but a larger increase in Ca_V channel activity on top of activation of PKA in mouse pancreatic β cells [154]. This means that the phosphorylation state of mouse β cell Ca_V channels under basal conditions is low [8].

β cell Ca_V channels are also regulated by tyrosine kinase receptors (Fig. 5) [8, 155–158]. The nerve growth factor signaling pathway is involved in β cell Ca_V channel regulation [8, 155, 156]. Long-term incubation (5–7 days) with nerve growth factor increases the density of Ca_V1 channels in the β cell plasma membrane, whereas the acute action of this nerve growth factor makes these channels more active [8, 155, 156]. Activation of insulin receptors with the insulin mimetic L-783,281 raises cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) in the mouse pancreatic β cell. The effect is significantly diminished by Ca_V1 channel blocker and absent in insulin receptor substrate-1-knockout β cells [8, 158]. However, the effect of acute activation of insulin receptors on β cell Ca_V channel activity has not been confirmed by patch-clamp analysis [8].

G protein-coupled receptors

The β cell is equipped with various G protein-coupled receptors, such as glucagon, glucagon-like peptide-1, somatostatin, opioid, galanin, adrenergic and muscarinic receptors [8, 159–177]. These receptors employ their partner G proteins as a brake on β cell Ca_V channel activity through physical association of G proteins with Ca_V channel pore-forming subunits (Fig. 5). They also regulate β cell Ca_V channel activity by manipulating protein kinases and second messengers (Fig. 5). Activation of glucagon, glucagon-like peptide-1 and opioid receptors enhances β cell Ca_V channel activity, whereas stimulation of galanin and α₂-adrenergic receptors reduces it. With regard to muscarinic receptors, their activation can either enhance or reduce β cell Ca_V channel activity dependent on cell types [8].

Exocytotic proteins

β Cell Ca_V1.2 and Ca_V1.3 channels physically associate with exocytotic proteins such as syntaxin 1A, SNAP-25 and synaptotagmin [178, 179]. The association of β cell Ca_V channels with exocytotic proteins functions as an exocytotic signalosome in β cells. Such an exocytotic signalosome transduces bidirectional signaling to fine-tune both β cell Ca_V1 channel activity and exocytotic protein interaction affinity [8, 178–180]. Ca_V channels not only serve as Ca²⁺ conduits to control insulin secretion via their mediated Ca²⁺ entry, but also as signaling devices to regulate the insulin secretory process independent of Ca²⁺ influx [63, 181, 182]. The conformational change of the Ca_V1.2 subunit, driven by Ca²⁺ binding and depolarization, can instantaneously signal to the exocytotic machinery to release an appreciable amount of insulin prior to Ca²⁺ influx. This innovative view is supported by the following findings. The inorganic Ca_V1 channel blocker La³⁺, which blocks Ca²⁺ influx by binding to the polyglutamate motif (EEEE) in the selectivity filter, significantly supports glucose-stimulated insulin secretion from rat pancreatic islets and ATP release in INS-1E cells. The effect is independent of Ca²⁺ release from intracellular stores and abolished by the organic Ca_V1 channel blocker nifedipine. This means that La³⁺ binding to the EEEE motif is sufficient to support glucose-stimulated insulin secretion at the very early phase [181, 182]. Intriguingly, the Ca_Vβ3 subunit is not likely to be a necessary building blocker of β cell Ca_V channels. Instead, it interacts with the intracellular Ca²⁺ release machinery serving as a brake of inositol 1,4,5-trisphosphate receptor-mediated Ca²⁺ mobilization from intracellular stores in the β cell and thus negatively regulates insulin secretion [63].

Glucose metabolism-derived signals

Glucose metabolism activates a range of β cell signaling pathways that possibly participate in the regulation of β cell Ca_V channels (Fig. 5). It seems that acute administration of high glucose increases β cell Ca_V channel activity [183]. Chronic exposure to high or low glucose inhibits expression of β cell Ca_V channels [8, 184, 185]. Glucose- or K⁺ depolarization-induced elevation in intracellular inositol hexakisphosphate acts as a critical mechanism for regulation of a variety of molecular and cellular functions including β cell Ca_V1 channel activity [7, 8, 186–193]. Elevated inositol hexakisphosphate enhances β cell Ca_V1 channel activity through inhibition of protein phosphatases and/or activation of the adenylyl cyclase-PKA cascade [189, 194]. Alterations in inositol polyphosphates in a β cell line lead to the up-regulation of Ca_V1 channel activity [195].

Components in blood plasma

In addition to glucose, several other components in blood plasma can regulate β cell Ca_V channels (Fig. 5). The serum protein transthyretin significantly increases β cell Ca_V channel activity and plays an important role in maintaining β cell function [196]. Free fatty acids act as regulators of β cell Ca_V channels. The most abundant saturated plasma free fatty acid palmitate produces dual effects on β cell Ca_V currents, namely stimulatory at lower and inhibitory at higher concentrations [197]. Cholesterol also regulates β cell Ca_V channels in two opposite directions [198, 199]. Chronic inhibition of cholesterol biosynthesis significantly reduces cholesterol in β cells. The resultant reduction of β cell cholesterol leads to a significant decrease in both β cell Ca_V channel activity and insulin exocytosis. The effect is effectively reversed by cholesterol repletion [199]. Exposure of mouse β cells to cholesterol-rich medium not only decreases glucose-stimulated mitochondrial ATP production, but also reduces β cell Ca_V channel activity [198]. These studies pinpoint that the β cell needs the appropriate amount of cholesterol and free fatty acids in blood plasma for its optimal function.

Ca²⁺ controls almost all known molecular and cellular events in the β cell

The complex Ca²⁺ signal generated by Ca²⁺ influx through Ca_V channels and Ca²⁺ release from intracellular stores varies through time and space in the β cell [200]. It controls almost all known molecular and cellular events in the β cell (Fig. 5). The Ca²⁺ signal takes center stage in insulin exocytosis and participates in β cell endocytosis, gene transcription, protein phosphorylation, mitosis, cell proliferation and differentiation to handle β cell homeostasis, development, survival and growth (Fig. 5) [7, 8]. Genetic or pharmacological ablation of voltage-dependent Ca²⁺ entry pathways results in overt defects in β cell development [8, 14, 139, 201]. The Ca_V1.3 and Ca_V2.3 channel knockout markedly impair postnatal pancreatic β cell generation and evidently retard islet cell differentiation, respectively [14, 139, 201]. The Ca_V1 channel blockers D-600 and diltiazem significantly slow down β cell proliferation [202, 203]. Hyperpolarization of β cells with the selective K_ATP channel opener diazoxide noticeably impedes β cell growth [202]. Expression of numerous β cell genes critically relies on Ca²⁺ influx through Ca_V channels [8, 204–207]. For example, Ca_V channel blockers effectively occlude insulin gene transcription induced by glucose stimulation [8, 204, 205].

[Ca²⁺]_i participates in not only molecular and cellular events that are essential, but also those that are dangerous for β cells [8]. Like other types of cells, the β cell only survives and functions in an appropriate range of [Ca²⁺]_i. When the β cell is filled with [Ca²⁺]_i either above or below this range, a set of molecules being in charge of cell demise becomes activated. A plethora of experimental evidence demonstrates that Ca²⁺ overload trigger apoptotic and necrotic β cell death through various Ca²⁺-sensitive enzymes, e.g., calcineurin, endonucleases, transglutaminase, and calpains [8, 208–211]. Calcineurin activated by the Ca²⁺ influx through β cell Ca_V1 channels mediates the IL-1β-induced β cell death [211]. Activation of Ca²⁺-dependent endonucleases by excessive Ca²⁺ influx through Ca_V1 channels induces pancreatic β cell apoptosis [209]. Transglutaminase 2 serves as a potential decoder of hyperactivated Ca_V channel-mediated Ca²⁺ entry in β cell apoptosis [208]. An apoptotic cascade arranged in the order of cytokine, PKC, Ca_V channels, calpain, calcineurin, Bad, cytochrome c, and caspase is present in insulin-secreting MIN6N8 cells [210].

Type 1 diabetic serum-induced apoptosis in β cells and underlying mechanisms have been well investigated [7, 8, 212–217]. Treatment with type 1 diabetic serum significantly increases the open probability of unitary Ca_V1 channels and the amplitude of whole-cell Ca_V1 currents in β cells. These hyperactivated Ca_V1 channels mediate exaggerated Ca²⁺ entry resulting in a Ca²⁺ overload in the β cell, manifested as abnormally elevated [Ca²⁺]_i. Consequently, the Ca²⁺ overload leads to typical β cell apoptosis characterized by DNA fragmentation. Furthermore, the type 1 diabetic serum-induced apoptosis is effectively prevented by the Ca_V1 channel blocker verapamil. It is clear that type 1 diabetic serum contains pathogenic factor(s), which drive Ca²⁺-dependent β cell destruction, via selective hyperactivation of β cell Ca_V1 channels, and thereby aggravation of diabetes (Fig. 5) [7, 8, 216]. Indeed, apolipoprotein CIII (ApoCIII) has been identified as a type 1 diabetic serum factor hyperactivating β cell Ca_V1 channels and thereby β cell apoptosis (Fig. 5) [8, 215]. ApoCIII levels are considerably elevated in type 1 diabetic serum. ApoCIII not only hyperactivates Ca_V1 channels but also increases their density in the β cell plasma membrane. The effect does not occur in β cells pretreated with the Ca_V1 channel blocker nimodipine or a mixture of PKA and Src. Furthermore, knockdown of β1 integrin or scavenger receptor class B type I (SR-BI) ablates ApoCIII-induced hyperactivation of β cell Ca_V1 channels. Apparently, ApoCIII hyperactivates β cell Ca_V1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src (Fig. 5) [212]. The occurrence of Ca²⁺ overload and apoptosis in ApoCIII-treated β cells and the abolishment of both type 1 diabetic serum- and ApoCIII-induced increases in [Ca²⁺]_i and apoptosis by anti-ApoCIII antibody verify the pathological consequence of ApoCIII-induced hyperactivation of β cell Ca_V1 channels [8, 215]. These studies provide evidence that the blood of type 1 diabetic patients aggravates the development of type 1 diabetes on top of a T-lymphocyte-mediated autoimmune attack [7, 8, 216].

The K_V2.1 channel serves as a brake for insulin secretion

During the β cell action potential, delayed rectifier K⁺ channel opening occurs subsequently to Ca_V channel opening. The resulting outward K⁺ current repolarizes the β cell plasma membrane [6]. Such a plasma membrane repolarization determines the duration of the β cell action potential and action potential-driven Ca²⁺ influx [19, 20, 22]. As such, the delayed rectifier K⁺ channel functions as a brake for glucose-stimulated insulin secretion [17, 18, 20, 22]. The islet β cell is equipped with several types of delayed rectifier K⁺ channels [6, 17, 20, 21]. Among them, the delayed rectifier K⁺ channel K_V 2.1 is the most abundant and mediates more than 80 % of delayed rectifier K⁺ currents [22]. Figure 1 shows that K_V2.1 channels open to mediate a K⁺ efflux as soon as the action potential reaches its peak. The K_V2.1 channel-mediated efflux causes the downstroke or repolarization phase of the action potential exhibited as a rapid decrease in the K_V2.1 conductance (gK_V2.1) (Fig. 1).

Structure and properties of β cell K_V2.1 channels

K_V2.1, the prevalent delayed rectifier K⁺ channel in β cells, belongs to the family of K_V channels (Fig. 4) [6, 22, 94]. It consists of four identical α subunits, each of which comprises six transmembrane segments S1–S6 structured as modular voltage-sensing (S1–S4) and pore-forming domains (S5–S6) (Fig. 4). The voltage-sensing domain (S1–S4) is characterized by multiple positively charged residues in S4. The pore-forming domain (S5–S6) carries a feature component called the S5–S6 linker that forms a selectivity filter at the narrowest part of the pore. In addition to these two key domains, this subunit also has a cytoplasmic tetramerization domain (T1) at the N-terminus and a long C-terminal cytoplasmic domain [218]. The former is distinct from the T1 domain of other K_V channels [219–222]. For example, the soluble K_V2.1 N-terminal fragment undergoes larger order oligomerization rather than tetramerization that occurs to other K_V N-terminal peptides [219–222]. The N-terminal and C-terminal cytoplasmic domains directly interact with each other to regulate cell surface expression, voltage-dependent activation gating and phosphorylation-dependent modulation of K_V2.1 [219]. In fact, this interaction is mediated by binding of a 34 amino acid motif in the juxtamembrane cytoplasmic C-terminus to a 17 amino acid motif in the N-terminal T1 domain at a position equivalent to the β subunit binding site in other K_V channels. It seems that the C-terminal cytoplasmic domain of K_V2.1 mimics the function of auxiliary β subunits of other K_V channels [219].

Three-dimensional images from electron micrographs show that K_V2.1 subunits are tetramerized as an egg-like shaped main body with a diameter of about 80 Å and a long axis of about 120 Å as viewed from the side. The upper one-third of the channel is embedded in the lipid bilayer [218]. The core of this part fits well with the X-ray structure of a closed KcsA that consists of only pore-forming domains [218, 223]. This means that the obtained structure of K_V2.1 channels is in a closed form. The perimeter of this part exhibits four upper arms corresponding to the S2 and S3 helices of K_V1.2 as revealed by comparison to the crystal structures of K_V1.2 [218, 224]. The lower two-third of the channel contains cytoplasmic N- and C-terminal domains of K_V2.1. The T1 domain of K_V1.2 is situated within the lower, narrower section of the K_V2.1 structure [218, 224]. There is a small internal chamber at the bottom of the T1 domain, which may represent the pathway for K⁺ entry into the pore of K_V2.1. Four lower arms stem from the lower two-third of K_V2.1 and are linked to the upper arms by the elbow of density formed by the T1-linker-S1 junction. The lower arm is mainly constituted by the C-terminal domain [218]. Clear contiguous density between the S4–S5 linker and the cytoplasmic density indicate that the direct association of these two domains is likely involved in channel gating [218].

In the mouse β cell, delayed rectifier K⁺ currents activate at potentials positive to −30 mV, increase linearly with depolarization from −30 to +70 mV and reach their peak amplitude of 210 ± 30 pA at −10 mV [2, 137]. Their activation satisfactorily follows n ² kinetics and has a time constant of about 2.5 ms at −20 mV [225]. The delayed rectifier K⁺ currents inactivate slowly with an exponential time constant of 5 s at +20 mV [2, 137]. It is well known that a majority of the delayed rectifier K⁺ currents flow through K_V2.1 channels [18, 19, 22]. In a low voltage range from −20 to +10 mV, all the delayed rectifier K⁺ currents likely pass through K_V2.1 channels since such K⁺ currents cannot be evoked by depolarization from −20 to +10 mV in the mouse β cell where K_V2.1 channels are ablated genetically or pharmacologically [18, 19, 22].

Function of β cell K_V2.1 channels

When glucose metabolism occurs in β cells, glucose-derived ATP efficiently depolarizes β cells resulting in sequential opening of their voltage-gated ion channels. Opening of β cell K_V2.1 channels generates slowly activating K⁺ currents that produce repolarization of the β cell action potential. Such repolarization shuts β cell Ca_V channels and consequently occludes the β cell Ca_V channel-mediated Ca²⁺ influx and its triggered insulin exocytosis [6, 17, 18, 20, 22]. Genetic ablation of K_V2.1 channels achieves an 83 % reduction in K_V currents in K_V2.1 knockout β cells. The K_V2.1 knockout β cell displays an evident increase in the glucose-induced action potential duration with in-phase mirror changes in the amplitude and duration of the depolarization-driven Ca²⁺ influx in K_V2.1 knockout β cells. Selective K_V2.1 channel blockers induce similar effects in wild type β cells. As consequence, K_V2.1 knockout islets secrete significantly more insulin in response to glucose stimulation. K_V2.1 knockout mice exhibit reduced fasting glucose levels and elevated serum insulin as well as improved glucose tolerance and glucose-stimulated insulin secretion [22]. There is no doubt that the K_V2.1 channel serves as a brake for insulin secretion in rodent β cells. However, recent data on K_V2.1 channels in human β cells reveal striking differences compared to mouse β cells. Human β cells indeed express K_V2.1 channels, but they express significantly more K_V2.2 channels [11, 13]. Importantly these K_V channels do not participate in action potential repolarization in human β cells [11, 13]. Unlike rodent β cells, human β cells employ BK channels to repolarize their plasma membrane building up the downstroke phase of the action potential [11, 13].

Regulation of β cell K_V2.1 channels

The β cell K_V2.1 channel is subjected to a diverse range of regulations (Fig. 5) [6]. Like other plasma membrane-standing ion channels, the β cell K_V2.1 K⁺-conducting pore and voltage sensors are embedded in the plasma membrane constituted by multiple lipids and its N- and C-terminal domains are surrounded by the complex intracellular milieu [226–231]. The lipid environment, intracellular milieu and extracellular surroundings are important for β cell K_V2.1 channel behavior [226–228, 231]. It seems that β cell K_V2.1 channels are situated in cholesterol-rich lipid rafts. Depletion of lipid rafts in the β cell plasma membrane markedly decreases the delayed rectifier K⁺ conductance and drastically increases insulin secretion (Fig. 5) [231]. β cell K_V2.1 channel gating is sensitive to temperature and redox state (Fig. 5) [227]. This channel mediates the majority of β cell K_V currents, which display little inactivation when recorded at room temperature, but exhibit both fast and slow inactivation at near-physiological temperatures [227]. Elevation of the intracellular redox state by increasing the intracellular NADPH/NADP⁺ ratio markedly facilitates both fast and slow inactivation [227].

Phosphorylation of β cell K_V2.1 channels is poorly understood. Indeed, the K_V2.1 channel carries 75 serine, 36 threonine, and 13 tyrosine residues in its cytoplasmic N- and C-terminal regions [226]. Many of them have been predicted to be potential phosphorylation sites [226]. Activation of glucagon-like peptide-1 receptors significantly decreases β cell K_V2.1 currents in a cAMP-dependent manner [232]. This opens up the possibility that β cell K_V2.1 channels may be regulated by PKA phosphorylation. Indeed, the free fatty acid linoleic acid can prominently down-regulate β cell K_V2.1 channel activity resulting in an increase in [Ca²⁺]_i and insulin secretion through stimulation of the orphan G protein-coupled receptor GPR40 and subsequent activation of PKA [233]. However, real phosphorylation of β cell K_V2.1 channels has not been verified experimentally. Interestingly, phospholipase A₂ cascade negatively regulates β cell K_V2.1 channels [228, 234]. Selective overexpression of this phospholipase A₂ in mouse β cells drastically speeds up β cell K_V2.1 channel inactivation and evidently reduces its amplitude following glucose stimulation. Consequently, prolonged duration and reduced frequency of the action potential as well as a more sustained elevation in [Ca²⁺]_i and increased insulin secretion occur to β cells overexpressing phospholipase A₂ [228, 234]. The effects are mimicked by the phospholipase A₂ reaction product arachidonic acid (Fig. 5) [228, 234].

Concluding remarks

Complex electrical signaling systems composed of intricate ionic events control insulin secretion and other β cell activities. These ionic events are organized mainly by ion channels in the β cell plasma membrane. β cell K_ATP channels open at rest to draw the membrane potential closer to the K⁺ equilibrium potential and farther from the firing threshold of action potentials. The K_ATP channels close, resulting in depolarization of the plasma membrane, when the ATP/ADP ratio rises with the energy load of the β cell (Fig. 1). If the ATP/ADP ratio is high enough to depolarize the β cell membrane to the firing threshold of action potentials, β cell Ca_V channels become activated. Ca²⁺ influx through the activated Ca_V channels leads to rapid further depolarization of the β cell plasma membrane forming the upstroke of the action potential (Fig. 1). Subsequently, K_V2.1 channels open. The resulting outward K⁺ current quickly repolarizes the β cell plasma membrane constituting the downstroke of the action potential (Fig. 1). Such a repolarization eventually closes β cell Ca_V channels. The action potential-driven Ca²⁺ influx takes center stage in insulin secretion. The complex Ca²⁺ signal generated by Ca²⁺ influx through Ca_V channels and Ca²⁺ release from intracellular stores in the β cell regulates all known molecular and cellular events, such as exocytosis, endocytosis, protein phosphorylation, gene expression, metabolism, differentiation, growth and even cell death (Fig. 5) [2–8]. K_ATP, Ca_V and K_V2.1 channels, three main classes of β cell ion channels, are regulated by a diverse range of mechanisms to generate distinct electrical signals under different physiological and pathological conditions (Fig. 5) [2–8, 13, 23, 95, 235, 236].

The current knowledge on β cell ionic mechanisms is almost exclusively acquired from in vitro studies. Caution should be exercised in extrapolating such knowledge to in vivo circumstances since factors in the blood, nerve innervation, and cellular networks surrounding pancreatic β cells have a great impact on β cell ionic mechanisms. It is a challenge to work on β cell ionic mechanisms in vivo due to technical difficulties. We set out to investigate ionic mechanisms in β cells within the islet transplanted into the anterior chamber of the eye of living animals by combining the patch-clamp technique and fluorescence microscopy (Yang et al. unpublished data) [237, 238].

Acknowledgments

Our research was supported by grants from Berth von Kantzow’s Foundation, Diabetes Research and Wellness Foundation, EuroDia (FP6-518153), European Research Council (ERC-2013-AdG), the Family Erling-Persson Foundation, Fredrik and Ingrid Thuring’s Foundation, Funds of Karolinska Institutet, the Knut and Alice Wallenberg Foundation, Magn. Bergvall’s Foundation, Novo Nordisk Foundation, Skandia Insurance Company, Ltd., the Stichting af Jochnick Foundation, Strategic Research Program in Diabetes at Karolinska Institutet, the Swedish Alzheimer Association, the Swedish Diabetes Association, the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Society of Medicine, Torsten and Ragnar Söderberg Foundation, VIBRANT (FP7-228933-2) and Åke Wiberg’s Foundation. P.-O. Berggren is founder of the Biotech Company BioCrine AB and is also a member of the board of this company. S.-N.Yang is a consultant to BioCrine AB. BioCrine AB is developing ApoCIII as a novel druggable target for the treatment of diabetes.

Abbreviations

AID: α₁-interaction domain
[Ca²⁺]_i: Cytosolic free Ca²⁺ concentration
CaMKII: Calcium/calmodulin-dependent kinase II
Ca_V: Voltage-gated Ca²⁺
gCa_V1: Ca_V1 channel conductance
gK_ATP: K_ATP channel conductance
gK_V2.1: K_V2.1 channel conductance
K_ATP: ATP-sensitive K⁺
K_V: Voltage-gated K⁺
Kir: Potassium inward rectifier
NBF: Nucleotide-binding fold
PIP₂: Phosphatidylinositol 4,5-bisphosphate
PKA: Protein kinase A
PKC: Protein kinase C
P-loop: Membrane-associated pore loop
SUR: Sulfonylurea receptor
TMD: Transmembrane domain

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PERMALINK

Ionic mechanisms in pancreatic β cell signaling

Shao-Nian Yang

Yue Shi

Guang Yang

Yuxin Li

Jia Yu

Per-Olof Berggren

Abstract

Introduction

Ionic mechanisms operate in various subcellular compartments of the β cell

Table 1.

KATP, CaV and KV channel-mediated ion fluxes

Ion fluxes through transient receptor potential (TRP) channels

A puzzling ion flux for initiation of β cell action potentials

Ca2+ mobilization from intracellular stores via inositol 1,4,5-trisphosphate receptor (IP3R) ion channels and ryanodine receptor (RyR) ion channels

ClC-3 Cl− channel-mediated Cl− entry into insulin granules

The KATP conductance determines the excitability of the β cell plasma membrane

Fig. 1.

Structure and properties of β cell KATP channels

Fig. 2.

Regulation of β cell KATP channels

Cytoplasmic nucleotides

Fig. 5.

Phosphatidylinositols

Actin cytoskeletal network

G protein-coupled receptors

Protein kinase A

Protein kinase C

Pharmacological blockers

Pharmacological openers

Ca2+ influx through β cell CaV channels mainly controls insulin secretion

Structure, classification and properties of β cell CaV channels

Fig. 3.

Regulation of insulin secretion by Ca2+ influx through β cell CaV channels

Regulation of β cell CaV channels

Protein kinases

G protein-coupled receptors

Exocytotic proteins

Glucose metabolism-derived signals

Components in blood plasma

Ca2+ controls almost all known molecular and cellular events in the β cell

The KV2.1 channel serves as a brake for insulin secretion

Structure and properties of β cell KV2.1 channels

Fig. 4.

Function of β cell KV2.1 channels

Regulation of β cell KV2.1 channels

Concluding remarks

Acknowledgments

Abbreviations

References

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

K_ATP, Ca_V and K_V channel-mediated ion fluxes

Ca²⁺ mobilization from intracellular stores via inositol 1,4,5-trisphosphate receptor (IP₃R) ion channels and ryanodine receptor (RyR) ion channels

ClC-3 Cl⁻ channel-mediated Cl⁻ entry into insulin granules

The K_ATP conductance determines the excitability of the β cell plasma membrane

Structure and properties of β cell K_ATP channels

Regulation of β cell K_ATP channels

Ca²⁺ influx through β cell Ca_V channels mainly controls insulin secretion

Structure, classification and properties of β cell Ca_V channels

Regulation of insulin secretion by Ca²⁺ influx through β cell Ca_V channels

Regulation of β cell Ca_V channels

Ca²⁺ controls almost all known molecular and cellular events in the β cell

The K_V2.1 channel serves as a brake for insulin secretion

Structure and properties of β cell K_V2.1 channels

Function of β cell K_V2.1 channels

Regulation of β cell K_V2.1 channels