Skip to main content
SpringerLink
Log in

ATP-Sensitive Potassium Channels in Health and Disease

Islets of Langerhans, 2. ed.

  • 90 Accesses

Abstract

The ATP-sensitive potassium (KATP) channel plays a crucial role in insulin secretion and thus glucose homeostasis. KATP channel activity in the pancreatic β-cell is finely balanced; increased activity prevents insulin secretion, whereas reduced activity stimulates insulin release. B-cell metabolism tightly regulates KATP channel gating, and if this coupling is perturbed, two distinct disease states can result. Diabetes occurs when the KATP channel fails to close in response to increased metabolism, whereas congenital hyperinsulinism results when KATP channels remain closed even at very low blood glucose levels. In general there is a good correlation between the magnitude of KATP current and disease severity. Mutations that cause a complete loss of KATP channels in the β-cell plasma membrane produce a severe form of congenital hyperinsulinism, whereas mutations that partially impair channel function produce a milder phenotype. Similarly mutations that greatly reduce the ATP sensitivity of the KATP channel lead to a severe form of neonatal diabetes with associated neurological complications, while mutations that cause smaller shifts in ATP sensitivity cause neonatal diabetes alone. This chapter reviews our current understanding of the pancreatic β-cell KATP channel and highlights recent structural, functional, and clinical advances.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

ABC:

ATP-binding cassette

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

CHI:

Congenital hyperinsulinism

CL3:

3rd Cytosolic loop in the sulphonylurea receptor connecting TMD0 to TMD1

DEND:

Developmental delay epilepsy and neonatal diabetes

GCK:

Glycolytic enzyme glucokinase

GIP:

Gastrointestinal peptide

GIRK:

G protein-coupled inwardly-rectifying potassium channel

GLP-1:

Glucagon-like peptide

GLUD1:

Mitochondrial glutamate dehydrogenase

HbA1C:

Glycosylated (or glycated) haemoglobin

i-DEND:

Intermediate DEND syndrome

KATP :

ATP-sensitive potassium

MRP:

Multidrug-resistant protein

NBD:

Nucleotide-binding domain

NBS:

Nucleotide-binding site

NDM:

Neonatal diabetes mellitus

PNDM:

Permanent neonatal diabetes mellitus

SCHAD:

Short-chain l-3-hydroxyacyl-CoA dehydrogenase

SUR:

Sulphonylurea receptor

TMD:

Transmembrane domain

TNDM:

Transient neonatal diabetes mellitus

References

  • Abdulhadi-Atwan M, Bushman J, Tornovsky-Babaey S et al (2008) Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. Diabetes 57:1935–1940

    CAS  PubMed  Google Scholar 

  • Abraham MR, Selivanov VA, Hodgson DM et al (2002) Coupling of cell energetics with membrane metabolic sensing. Integrative signaling through creatine kinase phosphotransfer disrupted by M-CK gene knock-out. J Biol Chem 277:24427–24434

    CAS  PubMed  Google Scholar 

  • Aguilar-Bryan L, Nichols CG, Wechsler SW et al (1995) Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268:423–426

    CAS  PubMed  Google Scholar 

  • Aittoniemi J, Fotinou C, Craig TJ et al (2009) Review. SUR1: a unique ATP-binding cassetteprotein that functions as an ion channel regulator. Philos Trans R Soc Lond 364:257–267

    CAS  Google Scholar 

  • Amoroso S, Schmid-Antomarchi H, Fosset M et al (1990) Glucose, sulfonylureas, and neurotransmitter release: role of ATP-sensitive K+ channels. Science 247:852–854

    CAS  PubMed  Google Scholar 

  • Antcliff JF, Haider S, Proks P et al (2005) Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO J 24:229–239

    CAS  PubMed  Google Scholar 

  • Ashcroft FM (2005) ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest 115:2047–2058

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ashcroft FM (2007) The Walter B. Cannon physiology in perspective lecture, 2007. ATP-sensitive K+ channels and disease: from molecule to malady. Am J Physiol Endocrinol Metab 293:E880–E889

    CAS  PubMed  Google Scholar 

  • Ashcroft FM, Rorsman P (1989) Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol 54:87–143

    CAS  PubMed  Google Scholar 

  • Ashcroft FM, Rorsman P (2004) Type 2 diabetes mellitus: not quite exciting enough? Hum Mol Genet 13(Spec No 1):R21–R31

    CAS  PubMed  Google Scholar 

  • Ashcroft FM, Harrison DE, Ashcroft SJ (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312:446–448

    CAS  PubMed  Google Scholar 

  • Avshalumov MV, Rice ME (2003) Activation of ATP-sensitive K+(KATP) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release. Proc Natl Acad Sci 100:11729–11734

    CAS  PubMed  Google Scholar 

  • Babenko AP (2008) A novel ABCC8 (SUR1)-dependent mechanism of metabolism-excitation uncoupling. J Biol Chem 283:8778–8782

    CAS  PubMed  Google Scholar 

  • Babenko AP, Bryan J (2002) SUR-dependent modulation of KATP channels by an N-terminal KiR6.2 peptide. Defining intersubunit gating interactions. J Biol Chem 277:43997–44004

    CAS  PubMed  Google Scholar 

  • Babenko AP, Bryan J (2003) Sur domains that associate with and gate KATP pores define a novel gatekeeper. J Biol Chem 278:41577–41580

    CAS  PubMed  Google Scholar 

  • Babenko AP, Vaxillaire M (2011) Mechanism of KATP hyperactivity and sulfonylure a tolerance due to a diabetogenic mutation in L0 helix of sulfonylurea receptor 1(ABCC8). FEBS Lett 585:3555–3559

    CAS  PubMed Central  PubMed  Google Scholar 

  • Babenko AP, Polak M, Cave H et al (2006) Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355:456–466

    CAS  PubMed  Google Scholar 

  • Barroso I, Luan J, Middelberg RP et al (2003) Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol 1:E20

    PubMed Central  PubMed  Google Scholar 

  • Bingham C, Hattersley AT (2004) Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant 19:2703–2708

    CAS  PubMed  Google Scholar 

  • Campbell JD, Sansom MS, Ashcroft FM (2003) Potassium channel regulation. EMBO Rep 4:1038–1042

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chutkow WA, Simon MC, Le Beau MM et al (1996) Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 45:1439–1445

    CAS  PubMed  Google Scholar 

  • Clark RH, McTaggart JS, Webster R et al (2010) Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin. Science 329:458–461

    CAS  PubMed  Google Scholar 

  • Clark R, Männikkö R, Stuckey DJ, Iberl M, Clarke K, Ashcroft FM (2012) Mice expressing a human KATP channel mutation have altered channel ATP sensitivity but no cardiac abnormalities. Diabetologia 55:1195–1204

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clement JP, Kunjilwar K, Gonzalez G et al (1997) Association and stoichiometry of KATP channel subunits. Neuron 18:827–838

    CAS  PubMed  Google Scholar 

  • Cook DL, Hales CN (1984) Intracellular ATP directly blocks K+ channels in pancreatic B-cells. Nature 311:271–273

    CAS  PubMed  Google Scholar 

  • Craig TJ, Ashcroft FM, Proks P (2008) How ATP inhibits the open KATP channel. J Gen Physiol 132:131–144

    CAS  PubMed Central  PubMed  Google Scholar 

  • de Wet H, Mikhailov MV, Fotinou C et al (2007a) Studies of the ATPase activity of the ABC proteinSUR1. FEBS J 274:3532–3544

    PubMed  Google Scholar 

  • de Wet H, Rees MG, Shimomura K et al (2007b) Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes. Proc Natl Acad Sci 104:18988–18992

    PubMed  Google Scholar 

  • de Wet H, Proks P, Lafond M et al (2008) A mutation (R826W) in nucleotide-binding domain1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes. EMBO Rep 9:648–654

    PubMed Central  PubMed  Google Scholar 

  • de Wet H, Shimomura K, Aittoniemi J et al (2012) A universally conserved residue in the SUR1 subunit of the KATP channel is essential for translating nucleotide binding at SUR1 into channel opening. J Physiol 590:5025–5036

    PubMed  Google Scholar 

  • Delepine M, Nicolino M, Barrett T et al (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25:406–409

    CAS  PubMed  Google Scholar 

  • Doyle DA, Morais Cabral J, Pfuetzner RA et al (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77

    CAS  PubMed  Google Scholar 

  • Drain P, Geng X, Li L (2004) Concerted gating mechanism underlying KATP channel inhibition by ATP. Biophys J 86:2101–2112

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dunne MJ, Cosgrove KE, Shepherd RM et al (2004) Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 84:239–275

    CAS  PubMed  Google Scholar 

  • Edghill EL, Gloyn AL, Gillespie KM (2004) Activating mutations in the KCNJ11 gene encoding the ATP-sensitive K+ channel subunit Kir6.2 are rare in clinically defined type 1 diabetes diagnosed before 2 years. Diabetes 53:2998–3001

    CAS  PubMed  Google Scholar 

  • Edghill EL, Flanagan SE, Ellard S (2010) Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. Rev Endocr Metab Disord 11:193–198

    CAS  PubMed  Google Scholar 

  • Ellard S, Flanagan SE, Girard CA et al (2007) Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet 81:375–382

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fatehi M, Raja M, Carter C et al (2012) The ATP-sensitive K+ channel ABCC8 S1369A type 2 diabetes risk variant increases MgATPase activity. Diabetes 61:241–249

    CAS  PubMed  Google Scholar 

  • Flanagan SE, Patch AM, Mackay DJ et al (2007) Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes 56:1930–1937

    CAS  PubMed  Google Scholar 

  • Girard CA, Shimomura K, Proks P et al (2006) Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch 453:323–332

    CAS  PubMed  Google Scholar 

  • Girard CA, Wunderlich FT, Shimomura K (2008) Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic β-cells recapitulates neonatal diabetes. J Clin Invest 119:80–90

    PubMed Central  PubMed  Google Scholar 

  • Glaser B, Kesavan P, Heyman M et al (1998) Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 338:226–230

    CAS  PubMed  Google Scholar 

  • Glaser B, Thornton P, Otonkoski T et al (2000) Genetics of neonatal hyperinsulinism. Arch Dis Child 82:F79–F86

    CAS  Google Scholar 

  • Gloyn AL, Weedon MN, Owen KR et al (2003) Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) andSUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52:568–572

    CAS  PubMed  Google Scholar 

  • Gloyn AL, Pearson ER, Antcliff J et al (2004a) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849

    CAS  PubMed  Google Scholar 

  • Gloyn AL, Cummings EA, Edghill EL et al (2004b) Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 89:3932–3935

    CAS  PubMed  Google Scholar 

  • Gloyn AL, Reimann F, Girard C et al (2005) Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Gen 14:925–934

    CAS  PubMed  Google Scholar 

  • Gloyn AL, Siddiqui J, Ellard S (2006) Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 27:220–231

    CAS  PubMed  Google Scholar 

  • Gopel SO, Kanno T, Barg S et al (2000a) Regulation of glucagon release in mouse α-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol 528:509–520

    CAS  PubMed  Google Scholar 

  • Gopel SO, Kanno T, Barg S et al (2000b) Patch-clamp characterisation of somatostatin-secreting D-cells in intact mouse pancreatic islets. J Physiol 528:497–507

    CAS  PubMed  Google Scholar 

  • Gribble FM, Tucker SJ, Ashcroft FM (1997) The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. EMBO J 16:1145–1152

    CAS  PubMed  Google Scholar 

  • Gribble FM, Williams L, Simpson AK et al (2003) A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLU Tag cell line. Diabetes 52:1147–1154

    CAS  PubMed  Google Scholar 

  • Griesemer D, Zawar C, Neumcke B (2002) Cell-type specific depression of neuronal excitability in rat hippocampus by activation of ATP-sensitive potassium channels. Eur Biophys J 31:467–477

    CAS  PubMed  Google Scholar 

  • Gumina RJ, Pucar D, Bast P et al (2003) Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics. Am J Physiol 284:H2106–H2113

    CAS  Google Scholar 

  • Hamming KS, Soliman D, Matemisz LC et al (2009) Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K+ channel. Diabetes 58:2419–2424

    CAS  PubMed  Google Scholar 

  • Hani EH, Boutin P, Durand E et al (1998) Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia 41:1511–1515

    CAS  PubMed  Google Scholar 

  • Hattersley AT, Ashcroft FM (2005) Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54:2503–2513

    CAS  PubMed  Google Scholar 

  • Henwood MJ, Kelly A, Macmullen C et al (2005) Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes. J Clin Endocrinol Metab 90:789–794

    CAS  PubMed  Google Scholar 

  • Hernandez-Sanchez C, Basile AS, Fedorova I et al (2001) Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death. Proc Natl Acad Sci 98:3549–3554

    CAS  PubMed  Google Scholar 

  • Heron-Milhavet L, Xue-Jun Y, Vannucci SJ et al (2004) Protection against hypoxic-ischemic injury in transgenic mice overexpressing Kir6.2 channel pore in forebrain. Mol Cell Neurosci 25:585–593

    CAS  PubMed  Google Scholar 

  • Huopio H, Reimann F, Ashfield R et al (2000) Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 106:897–906

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huopio H, Otonkoski T, Vauhkonen I et al (2003) A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 361:301–307

    CAS  PubMed  Google Scholar 

  • Inagaki N, Gonoi T, Clement JP (1995a) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270:1166–1170

    CAS  PubMed  Google Scholar 

  • Inagaki N, Tsuura Y, Namba N et al (1995b) Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J Biol Chem 270:5691–5694

    CAS  PubMed  Google Scholar 

  • Inagaki N, Gonoi T, Clement JP et al (1996) A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron 16:1011–1017

    CAS  PubMed  Google Scholar 

  • Isomoto S, Kondo C, Yamada M et al (1996) A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. J Biol Chem 271:24321–24324

    CAS  PubMed  Google Scholar 

  • John SA, Weiss JN, Ribalet B (2001) Regulation of cloned ATP-sensitive K channels by adenine nucleotides and sulfonylureas: interactions between SUR1 and positively charged domains on Kir6.2. J Gen Physiol 118:391–405

    CAS  PubMed Central  PubMed  Google Scholar 

  • John SA, Weiss JN, Xie LH et al (2003) Molecular mechanism for ATP-dependent closure of the K+ channel Kir6.2. J Physiol 552:23–34

    CAS  PubMed  Google Scholar 

  • Kanno T, Rorsman P, Gopel SO (2002a) Glucose-dependent regulation of rhythmic action potential firing in pancreatic beta-cells by KATP-channel modulation. J Physiol 545:501–507

    CAS  PubMed  Google Scholar 

  • Kanno T, Gopel SO, Rorsman P et al (2002b) Cellular function in multicellular system for hormone-secretion: electrophysiological aspect of studies on alpha-, beta- and delta-cells of the pancreatic islet. Neurosci Res 42:79–90

    CAS  PubMed  Google Scholar 

  • Klupa T, Warram JH, Antonellis A et al (2002) Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1 alpha mutations: evidence for parent-of-origin effect. Diabetes Care 25:2292–2301

    CAS  PubMed  Google Scholar 

  • Koster JC, Marshall BA, Ensor N et al (2000) Targeted overactivity of beta cell KATP channels induces profound neonatal diabetes. Cell 100:645–654

    CAS  PubMed  Google Scholar 

  • Koster JC, Knopp A, Flagg TP et al (2001) Tolerance for ATP-insensitive KATP channels in transgenic mice. Circ Res 89:1022–1029

    CAS  PubMed  Google Scholar 

  • Koster JC, Remedi MS, Flagg TP et al (2002) Hyperinsulinism induced by targeted suppression of beta cell KATP channels. Proc Natl Acad Sci 99:16992–16997

    CAS  PubMed  Google Scholar 

  • Koster JC, Remedi MS, Masia R et al (2006) Expression of ATP-insensitive KATP channels in pancreatic beta-cells underlies a spectrum of diabetic phenotypes. Diabetes 55:2957–2964

    CAS  PubMed  Google Scholar 

  • Koster JC, Kurata HT, Enkvetchakul D et al (2008) A DEND mutation in Kir6.2 (KCNJ11) reveals a flexible N-terminal region critical for ATP-sensing of the KATP channel. Biophys J 95:4689–4697

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kuo A, Gulbis JM, Antcliff JF et al (2003) Crystal structure of the potassium channel KirBac1.1in the closed state. Science 300:1922–1926

    CAS  PubMed  Google Scholar 

  • Li L, Geng X, Drain P (2002) Open state destabilization by ATP occupancy is mechanism speeding burst exit underlying KATP channel inhibition by ATP. J Gen Physiol 119:105–116

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lin YW, Bushman JD, Yan FF et al (2008) Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism. J Biol Chem 283:9146–9156

    CAS  PubMed  Google Scholar 

  • Lin YW, Akrouh A, Hsu Y et al (2012) Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic KATP channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1subunits. Channels 6:133–138

    CAS  PubMed  Google Scholar 

  • Liss B, Bruns R, Roeper J (1999) Alternative sulfonylurea receptor expression defines metabolic sensitivity of KATP channels in dopaminergic midbrain neurons. EMBO J 18:833–846

    CAS  PubMed  Google Scholar 

  • MacDonald PE, De Marinis YZ, Ramracheya R et al (2007) AK ATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol 5:e143

    PubMed Central  PubMed  Google Scholar 

  • Magge SN, Shyng SL, MacMullen C et al (2004) Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor. J Clin Endocrinol Metab 89:4450–4456

    CAS  PubMed  Google Scholar 

  • Männikkö R, Jefferies C, Flanagan SE, Hattersley A, Ellard S, Ashcroft FM (2010) Interaction between mutations in the slide helix of Kir6.2 associated with neonatal diabetes and neurological symptoms. Hum Mol Genet 19:963–972

    PubMed  Google Scholar 

  • Männikkö R, Stansfeld PJ, Ashcroft AS, Hattersley AT, Sansom MS, Ellard S (2011a) Ashcroft FM.A conserved tryptophan at the membrane-water interface acts as a gatekeeper for Kir6.2/SUR1 channels and causes neonatal diabetes when mutated. J Physiol 589:3071–3083

    PubMed  Google Scholar 

  • Männikkö R, Flanagan SE, Sim X et al (2011b) Mutations of the same conserved glutamate residue in NBD2 of the sulfonylurea receptor 1 subunit of the KATP channel can result in either hyperinsulinism or neonatal diabetes. Diabetes 60:1813–1822

    PubMed  Google Scholar 

  • Mao Q, Leslie EM, Deeley RG et al (1999) ATPase activity of purified and reconstituted multidrug resistance protein MRP1 from drug-selected H69AR cells. Biochim Biophys Acta 1461:69–82

    CAS  PubMed  Google Scholar 

  • Markworth E, Schwanstecher C, Schwanstecher M (2000) ATP4- mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites. Diabetes 49:1413–1418

    CAS  PubMed  Google Scholar 

  • Marthinet E, Bloc A, Oka Y et al (2005) Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function. J Clin Endocrinol Metab 90:5401–5406

    CAS  PubMed  Google Scholar 

  • Masia R, Koster JC, Tumini S et al (2007a) An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. Diabetes 56:328–336

    CAS  PubMed  Google Scholar 

  • Masia R, De Leon DD, MacMullen C et al (2007b) A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Diabetes 56:1357–1362

    CAS  PubMed  Google Scholar 

  • Matsuo M, Tanabe K, Kioka N et al (2000) Different binding properties and affinities for ATP and ADP among sulfonylurea receptor subtypes, SUR1, SUR2A, and SUR2B. J Biol Chem 275:28757–28763

    CAS  PubMed  Google Scholar 

  • Mikhailov MV, Campbell JD, de Wet H et al (2005) 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. EMBO J 24:4166–4175

    CAS  PubMed  Google Scholar 

  • Miki T, Seino S (2005) Roles of KATP channels as metabolic sensors in acute metabolic changes. J Mol Cell Cardiol 38:917–925

    CAS  PubMed  Google Scholar 

  • Miki T, Tashiro F, Iwanaga T et al (1997) Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. Proc Natl Acad Sci 94:11969–11973

    CAS  PubMed  Google Scholar 

  • Miki T, Nagashima K, Tashiro F et al (1998) Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc Natl Acad Sci 95:10402–10406

    CAS  PubMed  Google Scholar 

  • Miki T, Liss B, Minami K et al (2001) ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4:507–512

    CAS  PubMed  Google Scholar 

  • Miki T, Minami K, Zhang L et al (2002) ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab 283:E1178–E1184

    CAS  PubMed  Google Scholar 

  • Mlynarski W, Tarasov AI, Gach A et al (2007) Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11. Nat Clin Pract Neurol 3:640–645

    CAS  PubMed  Google Scholar 

  • Nenquin M, Szollosi A, Aguilar-Bryan L et al (2004) Both triggering and amplifying pathways contribute to fuel-induced insulin secretion in the absence of sulfonylurea receptor-1 in pancreatic beta-cells. J Biol Chem 279:32316–32324

    CAS  PubMed  Google Scholar 

  • Nestorowicz A, Inagaki N, Gonoi T et al (1997) A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 46:1743–1748

    CAS  PubMed  Google Scholar 

  • Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism. Nature 440:470–476

    CAS  PubMed  Google Scholar 

  • Nichols CG, Shyng SL, Nestorowicz A et al (1996) Adenosine diphosphate as an intracellular regulator of insulin secretion. Science 272:1785–1787

    CAS  PubMed  Google Scholar 

  • Nishida M, MacKinnon R (2002) Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution. Cell 111:957–965

    CAS  PubMed  Google Scholar 

  • Nishida M, Cadene M, Chait BT et al (2007) Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J 26:4005–4015

    CAS  PubMed  Google Scholar 

  • Njolstad PR, Sovik O, Cuesta-Munoz A et al (2001) Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 344:1588–1592

    CAS  PubMed  Google Scholar 

  • Njolstad PR, Sagen JV, Bjorkhaug L et al (2003) Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 52:2854–2860

    CAS  PubMed  Google Scholar 

  • Ortiz D, Voyvodic P, Gossack L et al (2012) Two neonatal diabetes mutations on transmembrane helix 15 of SUR1 increase affinity for ATP and ADP at nucleotide binding domain 2. J Biol Chem 287:17985–17995

    CAS  PubMed  Google Scholar 

  • Partridge CJ, Beech DJ, Sivaprasadarao A (2001) Identification and pharmacological correction of a membrane trafficking defect associated with a mutation in the sulfonylurea receptor causing familial hyperinsulinism. J Biol Chem 276:35947–35952

    CAS  PubMed  Google Scholar 

  • Pearson ER, Flechtner I, Njolstad PR et al (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355:467–477

    CAS  PubMed  Google Scholar 

  • Pegan S, Arrabit C, Zhou W et al (2005) Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nat Neurosci 8:279–287

    CAS  PubMed  Google Scholar 

  • Polak M, Shield J (2004) Neonatal and very-early-onset diabetes mellitus. Semin Neonatol 9:59–65

    PubMed  Google Scholar 

  • Porter JR, Shaw NJ, Barrett TG et al (2005) Permanent neonatal diabetes in an Asian infant. J Pediatr 146:131–133

    CAS  PubMed  Google Scholar 

  • Proks P, Ashcroft FM (1997) Phentolamine block of KATP channels is mediated by Kir6.2. Proc Natl Acad Sci 94:11716–11720

    CAS  PubMed  Google Scholar 

  • Proks P, Ashcroft FM (2009) Modeling KATP channel gating and its regulation. Prog Biophys Mol Biol 99:7–19

    CAS  PubMed  Google Scholar 

  • Proks P, Antcliff JF, Lippiat J et al (2004) Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci 101:17539–17544

    CAS  PubMed  Google Scholar 

  • Proks P, Girard C, Haider S et al (2005a) A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome. EMBO Rep 6:470–475

    CAS  PubMed Central  PubMed  Google Scholar 

  • Proks P, Girard C, Ashcroft FM (2005b) Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol Gen 14:2717–2726

    CAS  PubMed  Google Scholar 

  • Proks P, Girard C, Baevre H et al (2006a) Functional effects of mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11), causing neonatal diabetes, and response to sulfonylureatherapy. Diabetes 55:1731–1777

    CAS  PubMed  Google Scholar 

  • Proks P, Arnold AL, Bruining J et al (2006b) A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Gen 15:1793–1800

    CAS  PubMed  Google Scholar 

  • Proks P, Shimomura K, Craig TJ et al (2007) Mechanism of action of a sulphonylurea receptorSUR1 mutation (F132L) that causes DEND syndrome. Hum Mol Gen 16:2011–2019

    CAS  PubMed  Google Scholar 

  • Proks P, de Wet H, Ashcroft FM (2010) Activation of the KATP channel by Mg-nucleotide interaction with SUR1. J Gen Physiol 136:389–405

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rafiq M, Flanagan SE, Patch AM et al (2008) Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. Diabetes Care 31:204–209

    CAS  PubMed  Google Scholar 

  • Ravier MA, Nenquin M, Miki T et al (2009) Glucose controls cytosolic Ca2+ and insulin secretion in mouse islets lacking adenosine triphosphate-sensitive K+ channels owing to a knockout of the pore-forming subunit Kir6.2. Endocrinology 150:33–45

    CAS  PubMed  Google Scholar 

  • Reimann F, Tucker SJ, Proks P et al (1999) Involvement of the n-terminus of Kir6.2 in coupling to the sulphonylurea receptor. J Physiol 518:325–336

    CAS  PubMed  Google Scholar 

  • Remedi MS, Kurata HT, Scott A et al (2009) Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of KATP-induced neonatal diabetes mellitus. Cell Metab 9:140–151

    CAS  PubMed  Google Scholar 

  • Remedi MS, Agapova SE, Vyas AK, Hruz PW, Nichols CG (2011) Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes. Diabetes 60:2515–2522

    CAS  PubMed  Google Scholar 

  • Riedel MJ, Boora P, Steckley D et al (2003) Kir6.2 polymorphisms sensitize β-cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes? Diabetes 52:2630–2635

    CAS  PubMed  Google Scholar 

  • Rorsman P, Salehi SA, Abdulkader F et al (2008) KATP channels and glucose-regulated glucagon secretion. Trends Endocrinol Metab 19:277–284

    CAS  PubMed  Google Scholar 

  • Rosario LM, Barbosa RM, Antunes CM et al (2008) Regulation by glucose of oscillatory electrical activity and 5-HT/insulin release from single mouse pancreatic islets in absence of functional KATP channels. Endocr J 55:639–650

    CAS  PubMed  Google Scholar 

  • Sagen JV, Raeder H, Hathout E et al (2004) Permanent neonatal diabetes due to mutations inKCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713–2718

    CAS  PubMed  Google Scholar 

  • Sakura H, Ammala C, Smith PA et al (1995) Cloning and functional expression of the cDNAencoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett 377:338–344

    CAS  PubMed  Google Scholar 

  • Schmid-Antomarchi H, Amoroso S, Fosset M et al (1990) K+ channel openers activate brain sulfonylurea-sensitive K+ channels and block neurosecretion. Proc Natl Acad Sci 87:3489–3492

    CAS  PubMed  Google Scholar 

  • Schwanstecher C, Meyer U, Schwanstecher M (2002) KIR6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K+ channels. Diabetes 51:875–879

    CAS  PubMed  Google Scholar 

  • Seghers V, Nakazaki M, DeMayo F et al (2000) Sur1 knockout mice. A model for KATP channel-independent regulation of insulin secretion. J Biol Chem 275:9270–9277

    CAS  PubMed  Google Scholar 

  • Seino S, Miki T (2003) Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog Biophys Mol Biol 81:133–176

    CAS  PubMed  Google Scholar 

  • Seino S, Miki T (2004) Gene targeting approach to clarification of ion channel function: studies of Kir6.x null mice. J Physiol 554:295–300

    CAS  PubMed  Google Scholar 

  • Sellick GS, Barker KT, Stolte-Dijkstra I et al (2004) Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36:1301–1305

    CAS  PubMed  Google Scholar 

  • Shi NQ, Ye B, Makielski JC (2005) Function and distribution of the SUR isoforms and splice variants. J Mol Cell Cardiol 39:51–60

    CAS  PubMed  Google Scholar 

  • Shimomura K, Girard CA, Proks P et al (2006) Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects. Diabetes 55:1705–1712

    CAS  PubMed  Google Scholar 

  • Shimomura K, Horster F, de Wet H et al (2007) A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology 69:1342–1349

    CAS  PubMed  Google Scholar 

  • Shimomura K, Flanagan SE, Zadek B, Lethby M, Zubcevic L, Girard CA, Petz O, Mannikko R, Kapoor RR, Hussain K, Skae M, Clayton P, Hattersley A, Ellard S, Ashcroft FM (2009) Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism. EMBO Mol Med 1:166–177

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shimomura K, de Nanclares GP, Foutinou C, Caimari M, Castaño L, Ashcroft FM (2010) The first clinical case of a mutation at residue K185 of Kir6.2 (KCNJ11): a major ATP-binding residue. Diabet Med 27:225–229

    CAS  PubMed  Google Scholar 

  • Shyng S, Nichols CG (1997) Octameric stoichiometry of the KATP channel complex. J Gen Physiol 110:655–664

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shyng SL, Ferrigni T, Nichols CG (1997) Regulation of KATP channel activity by diazoxide and MgADP. Distinct functions of the two nucleotide binding folds of the sulfonylurea receptor. J Gen Physiol 110:643–654

    CAS  PubMed Central  PubMed  Google Scholar 

  • Slingerland AS, Nuboer R, Hadders-Algra M et al (2006) Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. Diabetologia 49:2559–2563

    CAS  PubMed  Google Scholar 

  • Stanley CA, Lieu YK, Hsu B et al (1998) Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352–1357

    CAS  PubMed  Google Scholar 

  • Stoffers DA, Zinkin NT, Stanojevic V (1997) Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 15:106–110

    CAS  PubMed  Google Scholar 

  • Suzuki M, Sasaki N, Miki T et al (2002) Role of sarcolemmal KATP channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest 109:509–516

    CAS  PubMed Central  PubMed  Google Scholar 

  • Szollosi A, Nenquin M, Aguilar-Bryan L et al (2007) Glucose stimulates Ca2+ influx and insulin secretion in 2-week-old beta-cells lacking ATP-sensitive K+ channels. J Biol Chem 282:1747–1756

    CAS  PubMed  Google Scholar 

  • Tammaro P, Girard C, Molnes J et al (2005) Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2-SUR1 interactions. EMBO J 24:2318–2330

    CAS  PubMed  Google Scholar 

  • Tammaro P, Flanagan SE, Zadek B et al (2008) A Kir6.2 mutation causing severe functional effects in vitro produces neonatal diabetes without the expected neurological complications. Diabetologia 51:802–810

    CAS  PubMed Central  PubMed  Google Scholar 

  • Taneja TK, Mankouri J, Karnik R et al (2009) Sar1-GTPase-dependent ER exit of KATP channels revealed by a mutation causing congenital hyperinsulinism. Hum Mol Genet 18:2400–2413

    CAS  PubMed  Google Scholar 

  • Tarasov A, Dusonchet J, Ashcroft FM (2004) Metabolic regulation of the pancreatic beta-cell ATP-sensitive K+ channel: a pas de deux. Diabetes 3(Suppl):S113–S122

    Google Scholar 

  • Tarasov AI, Girard CA, Ashcroft FM (2006a) ATP sensitivity of the ATP-sensitive K+ channel in intact and permeabilized pancreatic beta-cells. Diabetes 55:2446–2454

    CAS  PubMed  Google Scholar 

  • Tarasov AI, Welters HJ, Senkel S et al (2006b) A Kir6.2 mutation causing neonatal diabetes impairs electrical activity and insulin secretion from INS-1 beta-cells. Diabetes 55:3075–3082

    CAS  PubMed  Google Scholar 

  • Tarasov AI, Girard CA, Larkin B et al (2007) Functional analysis of two Kir6.2 (KCNJ11) mutations, K170T and E322K, causing neonatal diabetes. Diabetes Obes Metab 9(Suppl 2):46–55

    CAS  PubMed  Google Scholar 

  • Taschenberger G, Mougey A, Shen S et al (2002) Identification of a familial hyperinsulinism-causing mutation in the sulfonylurea receptor 1 that prevents normal trafficking and function of KATP channels. J Biol Chem 277:17139–17146

    CAS  PubMed  Google Scholar 

  • Temple IK, James RS, Crolla JA et al (1995) An imprinted gene(s) for diabetes? Nat Genet 9:110–112

    CAS  PubMed  Google Scholar 

  • Temple IK, Gardner RJ, Mackay DJ et al (2000) Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes 49:1359–1366

    CAS  PubMed  Google Scholar 

  • The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986

    Google Scholar 

  • Thomas PM, Cote GJ, Wohllk N et al (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268:426–429

    CAS  PubMed  Google Scholar 

  • Thomas PM, Ye Y, Lightner E (1996) Mutation of the pancreatic islet inward rectifier Kir6.2also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Gen 5:1809–1812

    CAS  PubMed  Google Scholar 

  • Trapp S, Proks P, Tucker SJ et al (1998) Molecular analysis of ATP-sensitive K channel gating and implications for channel inhibition by ATP. J Gen Physiol 112:333–349

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tucker SJ, Gribble FM, Zhao C et al (1997) Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature 387:179–183

    CAS  PubMed  Google Scholar 

  • UK Prospective Diabetes Study Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853

    Google Scholar 

  • Vaxillaire M, Populaire C, Busiah K et al (2004) Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes 53:2719–2722

    CAS  PubMed  Google Scholar 

  • Villareal DT, Koster JC, Robertson H et al (2009) Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance. Diabetes 58:1869–1878

    CAS  PubMed  Google Scholar 

  • Wang R, Liu X, Hentges ST et al (2004) The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes 53:1959–1965

    CAS  PubMed  Google Scholar 

  • Wildin RS, Ramsdell F, Peake J et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18–20

    CAS  PubMed  Google Scholar 

  • Yamada K, Ji JJ, Yuan H et al (2001) Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science 292:1543–1556

    CAS  PubMed  Google Scholar 

  • Yan F, Lin CW, Weisiger E et al (2004) Sulfonylureas correct trafficking defects of ATP-sensitive potassium channels caused by mutations in the sulfonylurea receptor. J Biol Chem 279:11096–11105

    CAS  PubMed  Google Scholar 

  • Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M, Yoshiharu A, Hosokawa M, Yanada Y, Inagaki N, Nakahete T (2005) The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2diabetes mellitus. J Clin Endocrinol Metab 90:3174–3178

    CAS  PubMed  Google Scholar 

  • Zawar C, Plant TD, Schirra C et al (1999) Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus. J Physiol 514(Pt 2):327–341

    CAS  PubMed  Google Scholar 

  • Zerangue N, Schwappach B, Jan YN et al (1999) A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron 22:537–548

    CAS  PubMed  Google Scholar 

  • Zhou Q, Garin I, Castaño L et al (2010) Neonatal diabetes caused by mutations in sulfonylurea receptor 1: interplay between expression and Mg-nucleotide gating defects of ATP-sensitive potassium channels. J Clin Endocrinol Metab 95:E473–E478

    CAS  PubMed  Google Scholar 

  • Zingman LV, Alekseev AE, Bienengraeber M et al (2001) Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance. Neuron 31:233–245

    CAS  PubMed  Google Scholar 

  • Zingman LV, Hodgson DM, Bast PH et al (2002) Kir6.2 is required for adaptation to stress. Proc Natl Acad Sci 99:13278–13283

    CAS  PubMed  Google Scholar 

  • Zung A, Glaser B, Nimri R et al (2004) Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab 89:5504–5507

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr Heidi de Wet for valuable comments about the manuscript.

Author information

Authors and Affiliations

  1. Department of Psychology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK

    Peter Proks

  2. University Laboratory of Physiology, Parks Road, Oxford, UK

    Rebecca Clark

Authors
  1. Peter Proks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rebecca Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Proks .

Editor information

Editors and Affiliations

  1. Södersjukhuset, Karolinska Institutet Dept. Clinical Research & Education, Stockholm, Sweden

    Md. Shahidul Islam

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Proks, P., Clark, R. (2013). ATP-Sensitive Potassium Channels in Health and Disease. In: Islam, M. (eds) Islets of Langerhans, 2. ed.. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6884-0_6-2

Download citation

  • DOI: https://doi.org/10.1007/978-94-007-6884-0_6-2

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Online ISBN: 978-94-007-6884-0

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Chapter history

  1. Latest

    ATP-Sensitive Potassium Channels in Health and Disease
    Published:
    15 April 2014

    DOI: https://doi.org/10.1007/978-94-007-6884-0_6-3

  2. Original

    ATP-Sensitive Potassium Channels in Health and Disease
    Published:
    14 February 2014

    DOI: https://doi.org/10.1007/978-94-007-6884-0_6-2

Search

Navigation