Skip to main content

Advertisement

Log in

Ionic mechanisms in pancreatic β cell signaling

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

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+ (KATP) channels, the voltage-gated Ca2+ (CaV) channel-mediated Ca2+ influx and K+ efflux through voltage-gated K+ (KV) 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 KATP channel-mediated K+ efflux determines the resting membrane potential and keeps the excitability of the β cell at low levels. Ca2+ influx through CaV1 channels, a major type of β cell CaV 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 KV2.1 delayed rectifier K+ channels, a predominant form of β cell KV 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 CaV 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 KATP channel-, CaV1 channel- and KV2.1 channel-mediated ion fluxes.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AID:

α1-interaction domain

[Ca2+] i :

Cytosolic free Ca2+ concentration

CaMKII:

Calcium/calmodulin-dependent kinase II

CaV :

Voltage-gated Ca2+

gCaV1:

CaV1 channel conductance

gKATP :

KATP channel conductance

gKV2.1:

KV2.1 channel conductance

KATP :

ATP-sensitive K+

KV :

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

References

  1. Drews G, Krippeit-Drews P, Dufer M (2010) Electrophysiology of islet cells. Adv Exp Med Biol 654:115–163

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  3. Aguilar-Bryan L, Bryan J (1999) Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 20:101–135

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  6. Jacobson DA, Philipson LH (2007) Action potentials and insulin secretion: new insights into the role of Kv channels. Diabetes Obes Metab 9:89–98

    PubMed  CAS  Google Scholar 

  7. Yang SN, Berggren PO (2005) β-Cell CaV channel regulation in physiology and pathophysiology. Am J Physiol 288:E16–E28

    CAS  Google Scholar 

  8. Yang SN, Berggren PO (2006) The role of voltage-gated calcium channels in pancreatic β-cell physiology and pathophysiology. Endocr Rev 27:621–676

    PubMed  CAS  Google Scholar 

  9. Philipson LH, Kusnetsov A, Larson T, Zeng Y, Westermark G (1993) Human, rodent, and canine pancreatic β-cells express a sodium channel α1-subunit related to a fetal brain isoform. Diabetes 42:1372–1377

    PubMed  CAS  Google Scholar 

  10. Alexander SP, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Catterall WA, Spedding M, Peters JA, Harmar AJ (2013) The Concise Guide to PHARMACOLOGY 2013/14: ion channels. Br J Pharmacol 170:1607–1651

    PubMed  CAS  Google Scholar 

  11. Braun M, Ramracheya R, Bengtsson M, Zhang Q, Karanauskaite J, Partridge C, Johnson PR, Rorsman P (2008) Voltage-gated ion channels in human pancreatic β-cells: electrophysiological characterization and role in insulin secretion. Diabetes 57:1618–1628

    PubMed  CAS  Google Scholar 

  12. Vignali S, Leiss V, Karl R, Hofmann F, Welling A (2006) Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells. J Physiol 572:691–706

    PubMed  CAS  PubMed Central  Google Scholar 

  13. Rorsman P, Braun M (2013) Regulation of insulin secretion in human pancreatic islets. Annu Rev Physiol 75:155–179

    PubMed  CAS  Google Scholar 

  14. Yang SN, Berggren PO (2005) CaV2.3 channel and PKCλ: new players in insulin secretion. J Clin Invest 115:16–20

    PubMed  CAS  PubMed Central  Google Scholar 

  15. Rorsman P, Eliasson L, Kanno T, Zhang Q, Gopel S (2011) Electrophysiology of pancreatic β-cells in intact mouse islets of Langerhans. Prog Biophys Mol Biol 107:224–235

    PubMed  CAS  Google Scholar 

  16. Tringham E, Powell KL, Cain SM, Kuplast K, Mezeyova J, Weerapura M, Eduljee C, Jiang X, Smith P, Morrison JL, Jones NC, Braine E, Rind G, Fee-Maki M, Parker D, Pajouhesh H, Parmar M, O’Brien TJ, Snutch TP (2012) T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures. Sci Transl Med 4:121ra119

    Google Scholar 

  17. MacDonald PE, Ha XF, Wang J, Smukler SR, Sun AM, Gaisano HY, Salapatek AM, Backx PH, Wheeler MB (2001) Members of the Kv1 and Kv2 voltage-dependent K+ channel families regulate insulin secretion. Mol Endocrinol 15:1423–1435

    PubMed  CAS  Google Scholar 

  18. MacDonald PE, Sewing S, Wang J, Joseph JW, Smukler SR, Sakellaropoulos G, Saleh MC, Chan CB, Tsushima RG, Salapatek AM, Wheeler MB (2002) Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic β-cells enhances glucose-dependent insulin secretion. J Biol Chem 277:44938–44945

    PubMed  CAS  Google Scholar 

  19. Tamarina NA, Kuznetsov A, Fridlyand LE, Philipson LH (2005) Delayed-rectifier (KV2.1) regulation of pancreatic β-cell calcium responses to glucose: inhibitor specificity and modeling. Am J Physiol Endocrinol Metab 289:E578–E585

    PubMed  CAS  Google Scholar 

  20. Roe MW, Worley JF 3rd, Mittal AA, Kuznetsov A, DasGupta S, Mertz RJ, Witherspoon SM 3rd, Blair N, Lancaster ME, McIntyre MS, Shehee WR, Dukes ID, Philipson LH (1996) Expression and function of pancreatic β-cell delayed rectifier K+ channels. Role in stimulus-secretion coupling. J Biol Chem 271:32241–32246

    PubMed  CAS  Google Scholar 

  21. Yan L, Figueroa DJ, Austin CP, Liu Y, Bugianesi RM, Slaughter RS, Kaczorowski GJ, Kohler MG (2004) Expression of voltage-gated potassium channels in human and rhesus pancreatic islets. Diabetes 53:597–607

    PubMed  CAS  Google Scholar 

  22. Jacobson DA, Kuznetsov A, Lopez JP, Kash S, Ammala CE, Philipson LH (2007) Kv2.1 ablation alters glucose-induced islet electrical activity, enhancing insulin secretion. Cell Metab 6:229–235

    PubMed  CAS  PubMed Central  Google Scholar 

  23. Ashcroft FM, Rorsman P (2013) KATP channels and islet hormone secretion: new insights and controversies. Nat Rev Endocrinol 9:660–669

    PubMed  CAS  Google Scholar 

  24. Dufer M, Gier B, Wolpers D, Krippeit-Drews P, Ruth P, Drews G (2009) Enhanced glucose tolerance by SK4 channel inhibition in pancreatic β-cells. Diabetes 58:1835–1843

    PubMed  PubMed Central  Google Scholar 

  25. Zhang M, Houamed K, Kupershmidt S, Roden D, Satin LS (2005) Pharmacological properties and functional role of Kslow current in mouse pancreatic β-cells: SK channels contribute to Kslow tail current and modulate insulin secretion. J Gen Physiol 126:353–363

    PubMed  CAS  PubMed Central  Google Scholar 

  26. Tamarina NA, Wang Y, Mariotto L, Kuznetsov A, Bond C, Adelman J, Philipson LH (2003) Small-conductance calcium-activated K+ channels are expressed in pancreatic islets and regulate glucose responses. Diabetes 52:2000–2006

    PubMed  CAS  Google Scholar 

  27. Gopel SO, Kanno T, Barg S, Eliasson L, Galvanovskis J, Renstrom E, Rorsman P (1999) Activation of Ca2+-dependent K+ channels contributes to rhythmic firing of action potentials in mouse pancreatic β cells. J Gen Physiol 114:759–770

    PubMed  CAS  PubMed Central  Google Scholar 

  28. Jacobson DA, Mendez F, Thompson M, Torres J, Cochet O, Philipson LH (2010) Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses. J Physiol 588:3525–3537

    PubMed  CAS  PubMed Central  Google Scholar 

  29. Cao DS, Zhong L, Hsieh TH, Abooj M, Bishnoi M, Hughes L, Premkumar LS (2012) Expression of transient receptor potential ankyrin 1 (TRPA1) and its role in insulin release from rat pancreatic beta cells. PLoS ONE 7:e38005

    PubMed  CAS  PubMed Central  Google Scholar 

  30. Colsoul B, Nilius B, Vennekens R (2013) Transient receptor potential (TRP) cation channels in diabetes. Curr Top Med Chem 13:258–269

    PubMed  CAS  Google Scholar 

  31. Colsoul B, Vennekens R, Nilius B (2011) Transient receptor potential cation channels in pancreatic β cells. Rev Physiol Biochem Pharmacol 161:87–110

    PubMed  Google Scholar 

  32. Roe MW, Worley JF, Qian F, Tamarina N, Mittal AA, Dralyuk F, Blair NT, Mertz RJ, Philipson LH, Dukes ID (1998) Characterization of a Ca2+ release-activated nonselective cation current regulating membrane potential and [Ca2+] i oscillations in transgenically derived β-cells. J Biol Chem 273:10402–10410

    PubMed  CAS  Google Scholar 

  33. Lange I, Yamamoto S, Partida-Sanchez S, Mori Y, Fleig A, Penner R (2009) TRPM2 functions as a lysosomal Ca2+-release channel in β cells. Sci Signal 2:ra23

    PubMed  PubMed Central  Google Scholar 

  34. Uchida K, Dezaki K, Damdindorj B, Inada H, Shiuchi T, Mori Y, Yada T, Minokoshi Y, Tominaga M (2011) Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice. Diabetes 60:119–126

    PubMed  CAS  PubMed Central  Google Scholar 

  35. Wagner TF, Drews A, Loch S, Mohr F, Philipp SE, Lambert S, Oberwinkler J (2010) TRPM3 channels provide a regulated influx pathway for zinc in pancreatic beta cells. Pflugers Arch 460:755–765

    PubMed  CAS  Google Scholar 

  36. Wagner TF, Loch S, Lambert S, Straub I, Mannebach S, Mathar I, Dufer M, Lis A, Flockerzi V, Philipp SE, Oberwinkler J (2008) Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic β cells. Nat Cell Biol 10:1421–1430

    PubMed  CAS  Google Scholar 

  37. Vennekens R, Olausson J, Meissner M, Bloch W, Mathar I, Philipp SE, Schmitz F, Weissgerber P, Nilius B, Flockerzi V, Freichel M (2007) Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat Immunol 8:312–320

    PubMed  CAS  Google Scholar 

  38. Cheng H, Beck A, Launay P, Gross SA, Stokes AJ, Kinet JP, Fleig A, Penner R (2007) TRPM4 controls insulin secretion in pancreatic β-cells. Cell Calcium 41:51–61

    PubMed  CAS  Google Scholar 

  39. Brixel LR, Monteilh-Zoller MK, Ingenbrandt CS, Fleig A, Penner R, Enklaar T, Zabel BU, Prawitt D (2010) TRPM5 regulates glucose-stimulated insulin secretion. Pflugers Arch 460:69–76

    PubMed  CAS  Google Scholar 

  40. Colsoul B, Schraenen A, Lemaire K, Quintens R, Van Lommel L, Segal A, Owsianik G, Talavera K, Voets T, Margolskee RF, Kokrashvili Z, Gilon P, Nilius B, Schuit FC, Vennekens R (2010) Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice. Proc Natl Acad Sci USA 107:5208–5213

    PubMed  CAS  PubMed Central  Google Scholar 

  41. Akiba Y, Kato S, Katsube K, Nakamura M, Takeuchi K, Ishii H, Hibi T (2004) Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet β cells modulates insulin secretion in rats. Biochem Biophys Res Commun 321:219–225

    PubMed  CAS  Google Scholar 

  42. Aoyagi K, Ohara-Imaizumi M, Nishiwaki C, Nakamichi Y, Nagamatsu S (2010) Insulin/phosphoinositide 3-kinase pathway accelerates the glucose-induced first-phase insulin secretion through TrpV2 recruitment in pancreatic β-cells. Biochem J 432:375–386

    PubMed  CAS  Google Scholar 

  43. Casas S, Novials A, Reimann F, Gomis R, Gribble FM (2008) Calcium elevation in mouse pancreatic beta cells evoked by extracellular human islet amyloid polypeptide involves activation of the mechanosensitive ion channel TRPV4. Diabetologia 51:2252–2262

    PubMed  CAS  Google Scholar 

  44. Zhang Y, Liu Y, Qu J, Hardy A, Zhang N, Diao J, Strijbos PJ, Tsushima R, Robinson RB, Gaisano HY, Wang Q, Wheeler MB (2009) Functional characterization of hyperpolarization-activated cyclic nucleotide-gated channels in rat pancreatic β cells. J Endocrinol 203:45–53

    PubMed  CAS  PubMed Central  Google Scholar 

  45. El-Kholy W, MacDonald PE, Fox JM, Bhattacharjee A, Xue T, Gao X, Zhang Y, Stieber J, Li RA, Tsushima RG, Wheeler MB (2007) Hyperpolarization-activated cyclic nucleotide-gated channels in pancreatic β-cells. Mol Endocrinol 21:753–764

    PubMed  CAS  Google Scholar 

  46. Coddou C, Yan Z, Obsil T, Huidobro-Toro JP, Stojilkovic SS (2011) Activation and regulation of purinergic P2X receptor channels. Pharmacol Rev 63:641–683

    PubMed  CAS  PubMed Central  Google Scholar 

  47. Silva AM, Rodrigues RJ, Tome AR, Cunha RA, Misler S, Rosario LM, Santos RM (2008) Electrophysiological and immunocytochemical evidence for P2X purinergic receptors in pancreatic β cells. Pancreas 36:279–283

    PubMed  CAS  Google Scholar 

  48. Inagaki N, Kuromi H, Gonoi T, Okamoto Y, Ishida H, Seino Y, Kaneko T, Iwanaga T, Seino S (1995) Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB J 9:686–691

    PubMed  CAS  Google Scholar 

  49. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405–496

    PubMed  CAS  PubMed Central  Google Scholar 

  50. Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud’homme GJ, Wang Q (2011) GABA exerts protective and regenerative effects on islet β cells and reverses diabetes. Proc Natl Acad Sci USA 108:11692–11697

    PubMed  CAS  PubMed Central  Google Scholar 

  51. Braun M, Ramracheya R, Bengtsson M, Clark A, Walker JN, Johnson PR, Rorsman P (2010) γ-Aminobutyric acid (GABA) is an autocrine excitatory transmitter in human pancreatic β-cells. Diabetes 59:1694–1701

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (1998) International Union of Pharmacology. XV. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev 50:291–313

    PubMed  CAS  Google Scholar 

  53. Best L, Sheader EA, Brown PD (1996) A volume-activated anion conductance in insulin-secreting cells. Pflugers Arch 431:363–370

    PubMed  CAS  Google Scholar 

  54. Kinard TA, Satin LS (1995) An ATP-sensitive Cl channel current that is activated by cell swelling, cAMP, and glyburide in insulin-secreting cells. Diabetes 44:1461–1466

    PubMed  CAS  Google Scholar 

  55. Britsch S, Krippeit-Drews P, Gregor M, Lang F, Drews G (1994) Effects of osmotic changes in extracellular solution on electrical activity of mouse pancreatic B-cells. Biochem Biophys Res Commun 204:641–645

    PubMed  CAS  Google Scholar 

  56. Best L, Brown PD, Sener A, Malaisse WJ (2010) Electrical activity in pancreatic islet cells: the VRAC hypothesis. Islets 2:59–64

    PubMed  Google Scholar 

  57. Boom A, Lybaert P, Pollet JF, Jacobs P, Jijakli H, Golstein PE, Sener A, Malaisse WJ, Beauwens R (2007) Expression and localization of cystic fibrosis transmembrane conductance regulator in the rat endocrine pancreas. Endocrine 32:197–205

    PubMed  CAS  Google Scholar 

  58. Verkman AS, Galietta LJ (2009) Chloride channels as drug targets. Nat Rev Drug Discov 8:153–171

    PubMed  CAS  PubMed Central  Google Scholar 

  59. Varadi A, Grant A, McCormack M, Nicolson T, Magistri M, Mitchell KJ, Halestrap AP, Yuan H, Schwappach B, Rutter GA (2006) Intracellular ATP-sensitive K+ channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis. Diabetologia 49:1567–1577

    PubMed  CAS  Google Scholar 

  60. Quesada I, Rovira JM, Martin F, Roche E, Nadal A, Soria B (2002) Nuclear KATP channels trigger nuclear Ca2+ transients that modulate nuclear function. Proc Natl Acad Sci USA 99:9544–9549

    PubMed  CAS  PubMed Central  Google Scholar 

  61. Soria B, Quesada I, Ropero AB, Pertusa JA, Martin F, Nadal A (2004) Novel players in pancreatic islet signaling: from membrane receptors to nuclear channels. Diabetes 53:S86–S91

    PubMed  CAS  Google Scholar 

  62. Barker CJ, Berggren PO (2013) New horizons in cellular regulation by inositol polyphosphates: insights from the pancreatic β-cell. Pharmacol Rev 65:641–669

    PubMed  CAS  Google Scholar 

  63. Berggren PO, Yang SN, Murakami M, Efanov AM, Uhles S, Kohler M, Moede T, Fernstrom A, Appelskog IB, Aspinwall CA, Zaitsev SV, Larsson O, Moitoso de Vargas L, Fecher-Trost C, Weissgerber P, Ludwig A, Leibiger B, Juntti-Berggren L, Barker CJ, Gromada J, Freichel M, Leibiger IB, Flockerzi V (2004) Removal of Ca2+ channel β3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis. Cell 119:273–284

    PubMed  CAS  Google Scholar 

  64. Mitchell KJ, Lai FA, Rutter GA (2003) Ryanodine receptor type I and nicotinic acid adenine dinucleotide phosphate receptors mediate Ca2+ release from insulin-containing vesicles in living pancreatic β-cells (MIN6). J Biol Chem 278:11057–11064

    PubMed  CAS  Google Scholar 

  65. Van Petegem F (2012) Ryanodine receptors: structure and function. J Biol Chem 287:31624–31632

    PubMed  PubMed Central  Google Scholar 

  66. Geng X, Li L, Watkins S, Robbins PD, Drain P (2003) The insulin secretory granule is the major site of KATP channels of the endocrine pancreas. Diabetes 52:767–776

    PubMed  CAS  Google Scholar 

  67. Barg S, Huang P, Eliasson L, Nelson DJ, Obermuller S, Rorsman P, Thevenod F, Renstrom E (2001) Priming of insulin granules for exocytosis by granular Cl uptake and acidification. J Cell Sci 114:2145–2154

    PubMed  CAS  Google Scholar 

  68. Thevenod F (2002) Ion channels in secretory granules of the pancreas and their role in exocytosis and release of secretory proteins. Am J Physiol Cell Physiol 283:C651–C672

    PubMed  CAS  Google Scholar 

  69. Li DQ, Jing X, Salehi A, Collins SC, Hoppa MB, Rosengren AH, Zhang E, Lundquist I, Olofsson CS, Morgelin M, Eliasson L, Rorsman P, Renstrom E (2009) Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. Cell Metab 10:309–315

    PubMed  Google Scholar 

  70. Deriy LV, Gomez EA, Jacobson DA, Wang X, Hopson JA, Liu XY, Zhang G, Bindokas VP, Philipson LH, Nelson DJ (2009) The granular chloride channel ClC-3 is permissive for insulin secretion. Cell Metab 10:316–323

    PubMed  CAS  PubMed Central  Google Scholar 

  71. Blondel O, Moody MM, Depaoli AM, Sharp AH, Ross CA, Swift H, Bell GI (1994) Localization of inositol trisphosphate receptor subtype 3 to insulin and somatostatin secretory granules and regulation of expression in islets and insulinoma cells. Proc Natl Acad Sci USA 91:7777–7781

    PubMed  CAS  PubMed Central  Google Scholar 

  72. Mitchell KJ, Pinton P, Varadi A, Tacchetti C, Ainscow EK, Pozzan T, Rizzuto R, Rutter GA (2001) Dense core secretory vesicles revealed as a dynamic Ca2+ store in neuroendocrine cells with a vesicle-associated membrane protein aequorin chimaera. J Cell Biol 155:41–51

    PubMed  CAS  PubMed Central  Google Scholar 

  73. Yang SN, Wenna ND, Yu J, Yang G, Qiu H, Yu L, Juntti-Berggren L, Kohler M, Berggren PO (2007) Glucose recruits KATP channels via non-insulin-containing dense-core granules. Cell Metab 6:217–228

    PubMed  CAS  Google Scholar 

  74. Ahmed M, Muhammed SJ, Kessler B, Salehi A (2010) Mitochondrial proteome analysis reveals altered expression of voltage dependent anion channels in pancreatic β-cells exposed to high glucose. Islets 2:283–292

    PubMed  Google Scholar 

  75. Kim WH, Lee JW, Suh YH, Hong SH, Choi JS, Lim JH, Song JH, Gao B, Jung MH (2005) Exposure to chronic high glucose induces β-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic β-cells. Diabetes 54:2602–2611

    PubMed  CAS  Google Scholar 

  76. O’Rourke B (2007) Mitochondrial ion channels. Annu Rev Physiol 69:19–49

    PubMed  PubMed Central  Google Scholar 

  77. Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364

    PubMed  CAS  Google Scholar 

  78. Nita II, Hershfinkel M, Kantor C, Rutter GA, Lewis EC, Sekler I (2014) Pancreatic β-cell Na+ channels control global Ca2+ signaling and oxidative metabolism by inducing Na+ and Ca2+ responses that are propagated into mitochondria. FASEB J (Epub ahead of print)

  79. Kullin M, Li Z, Hansen JB, Bjork E, Sandler S, Karlsson FA (2000) KATP channel openers protect rat islets against the toxic effect of streptozotocin. Diabetes 49:1131–1136

    PubMed  CAS  Google Scholar 

  80. Quesada I, Soria B (2004) Intracellular location of KATP channels and sulphonylurea receptors in the pancreatic β-cell: new targets for oral antidiabetic agents. Curr Med Chem 11:2707–2716

    PubMed  CAS  Google Scholar 

  81. Pi J, Bai Y, Zhang Q, Wong V, Floering LM, Daniel K, Reece JM, Deeney JT, Andersen ME, Corkey BE, Collins S (2007) Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes 56:1783–1791

    PubMed  CAS  Google Scholar 

  82. Toth B, Csanady L (2010) Identification of direct and indirect effectors of the transient receptor potential melastatin 2 (TRPM2) cation channel. J Biol Chem 285:30091–30102

    PubMed  CAS  PubMed Central  Google Scholar 

  83. Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, Kinet JP, Scharenberg AM (2001) ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411:595–599

    PubMed  CAS  Google Scholar 

  84. Best L (2005) Glucose-induced electrical activity in rat pancreatic β-cells: dependence on intracellular chloride concentration. J Physiol 568:137–144

    PubMed  CAS  PubMed Central  Google Scholar 

  85. Gall D, Gromada J, Susa I, Rorsman P, Herchuelz A, Bokvist K (1999) Significance of Na/Ca exchange for Ca2+ buffering and electrical activity in mouse pancreatic β-cells. Biophys J 76:2018–2028

    PubMed  CAS  PubMed Central  Google Scholar 

  86. Best L, Miley HE, Yates AP (1996) Activation of an anion conductance and β-cell depolarization during hypotonically induced insulin release. Exp Physiol 81:927–933

    PubMed  CAS  Google Scholar 

  87. Ashcroft FM, Rorsman P (1990) ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion. Biochem Soc Trans 18:109–111

    PubMed  CAS  Google Scholar 

  88. Rorsman P, Berggren PO, Bokvist K, Efendic S (1990) ATP-regulated K+ channels and diabetes mellitus. News Physiol Sci 5:143–147

    CAS  Google Scholar 

  89. Gilon P, Ravier MA, Jonas JC, Henquin JC (2002) Control mechanisms of the oscillations of insulin secretion in vitro and in vivo. Diabetes 51:S144–S151

    PubMed  CAS  Google Scholar 

  90. Zhang M, Goforth P, Bertram R, Sherman A, Satin L (2003) The Ca2+ dynamics of isolated mouse β-cells and islets: implications for mathematical models. Biophys J 84:2852–2870

    PubMed  CAS  PubMed Central  Google Scholar 

  91. Beauvois MC, Merezak C, Jonas JC, Ravier MA, Henquin JC, Gilon P (2006) Glucose-induced mixed [Ca2+]c oscillations in mouse β-cells are controlled by the membrane potential and the SERCA3 Ca2+-ATPase of the endoplasmic reticulum. Am J Physiol Cell Physiol 290:C1503–C1511

    PubMed  CAS  Google Scholar 

  92. Poea-Guyon S, Ammar MR, Erard M, Amar M, Moreau AW, Fossier P, Gleize V, Vitale N, Morel N (2013) The V-ATPase membrane domain is a sensor of granular pH that controls the exocytotic machinery. J Cell Biol 203:283–298

    PubMed  CAS  PubMed Central  Google Scholar 

  93. Hille B (2001) Ion channels of excitable membranes. Sinauer, Sunderland

    Google Scholar 

  94. Jan LY, Jan YN (2012) Voltage-gated potassium channels and the diversity of electrical signalling. J Physiol 590:2591–2599

    PubMed  CAS  PubMed Central  Google Scholar 

  95. Nichols CG, Remedi (2012) The diabetic β-cell: hyperstimulated vs. hyperexcited. Diabetes Obes Metab 14(Suppl 3):129–135

    PubMed  CAS  PubMed Central  Google Scholar 

  96. Smith PA, Ashcroft FM, Rorsman P (1990) Simultaneous recordings of glucose dependent electrical activity and ATP-regulated K+-currents in isolated mouse pancreatic β-cells. FEBS Lett 261:187–190

    PubMed  CAS  Google Scholar 

  97. Mikhailov MV, Campbell JD, de Wet H, Shimomura K, Zadek B, Collins RF, Sansom MS, Ford RC, Ashcroft FM (2005) 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. EMBO J 24:4166–4175

    PubMed  CAS  PubMed Central  Google Scholar 

  98. Ashcroft SJ, Ashcroft FM (1990) Properties and functions of ATP-sensitive K-channels. Cell Signal 2:197–214

    PubMed  CAS  Google Scholar 

  99. Rorsman P, Trube G (1985) Glucose dependent K+-channels in pancreatic β-cells are regulated by intracellular ATP. Pflugers Arch 405:305–309

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  102. Bokvist K, Rorsman P, Smith PA (1990) Block of ATP-regulated and Ca2+-activated K+ channels in mouse pancreatic β-cells by external tetraethylammonium and quinine. J Physiol 423:327–342

    PubMed  CAS  PubMed Central  Google Scholar 

  103. Misler S, Falke LC, Gillis K, McDaniel ML (1986) A metabolite-regulated potassium channel in rat pancreatic B cells. Proc Natl Acad Sci USA 83:7119–7123

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Arkhammar P, Nilsson T, Rorsman P, Berggren PO (1987) Inhibition of ATP-regulated K+ channels precedes depolarization-induced increase in cytoplasmic free Ca2+ concentration in pancreatic β-cells. J Biol Chem 262:5448–5454

    PubMed  CAS  Google Scholar 

  105. Trube G, Rorsman P, Ohno-Shosaku T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic β-cells. Pflugers Arch 407:493–499

    PubMed  CAS  Google Scholar 

  106. Ashcroft FM, Kakei M, Gibson JS, Gray DW, Sutton R (1989) The ATP- and tolbutamide-sensitivity of the ATP-sensitive K-channel from human pancreatic B cells. Diabetologia 32:591–598

    PubMed  CAS  Google Scholar 

  107. Ashcroft FM, Ashcroft SJ, Harrison DE (1988) Properties of single potassium channels modulated by glucose in rat pancreatic β-cells. J Physiol 400:501–527

    PubMed  CAS  PubMed Central  Google Scholar 

  108. Ashcroft FM (2006) KATP channels and insulin secretion: a key role in health and disease. Biochem Soc Trans 34:243–246

    PubMed  CAS  Google Scholar 

  109. Wilson JE, Chin A (1991) Chelation of divalent cations by ATP, studied by titration calorimetry. Anal Biochem 193:16–19

    PubMed  CAS  Google Scholar 

  110. Storer AC, Cornish-Bowden A (1976) Concentration of MgATP2− and other ions in solution. Calculation of the true concentrations of species present in mixtures of associating ions. Biochem J 159:1–5

    PubMed  CAS  PubMed Central  Google Scholar 

  111. Tarasov A, Dusonchet J, Ashcroft F (2004) Metabolic regulation of the pancreatic β-cell ATP-sensitive K+ channel: a pas de deux. Diabetes 53:S113–S122

    PubMed  CAS  Google Scholar 

  112. Shyng SL, Nichols CG (1998) Membrane phospholipid control of nucleotide sensitivity of KATP channels. Science 282:1138–1141

    PubMed  CAS  Google Scholar 

  113. Baukrowitz T, Schulte U, Oliver D, Herlitze S, Krauter T, Tucker SJ, Ruppersberg JP, Fakler B (1998) PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science 282:1141–1144

    PubMed  CAS  Google Scholar 

  114. Furukawa T, Yamane T, Terai T, Katayama Y, Hiraoka M (1996) Functional linkage of the cardiac ATP-sensitive K+ channel to the actin cytoskeleton. Pflugers Arch 431:504–512

    PubMed  CAS  Google Scholar 

  115. Nakano K, Suga S, Takeo T, Ogawa Y, Suda T, Kanno T, Wakui M (2002) Intracellular Ca2+ modulation of ATP-sensitive K+ channel activity in acetylcholine-induced activation of rat pancreatic β-cells. Endocrinology 143:569–576

    PubMed  CAS  Google Scholar 

  116. Petit P, Hillaire-Buys D, Manteghetti M, Debrus S, Chapal J, Loubatieres-Mariani MM (1998) Evidence for two different types of P2 receptors stimulating insulin secretion from pancreatic B cell. Br J Pharmacol 125:1368–1374

    PubMed  CAS  PubMed Central  Google Scholar 

  117. Burnstock G (2014) Purinergic signalling in endocrine organs. Purinergic Signal 10:189–231

    PubMed  CAS  PubMed Central  Google Scholar 

  118. Beguin P, Nagashima K, Nishimura M, Gonoi T, Seino S (1999) PKA-mediated phosphorylation of the human KATP channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. EMBO J 18:4722–4732

    PubMed  CAS  PubMed Central  Google Scholar 

  119. Ozaki N, Shibasaki T, Kashima Y, Miki T, Takahashi K, Ueno H, Sunaga Y, Yano H, Matsuura Y, Iwanaga T, Takai Y, Seino S (2000) cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat Cell Biol 2:805–811

    PubMed  CAS  Google Scholar 

  120. Hu K, Huang CS, Jan YN, Jan LY (2003) ATP-sensitive potassium channel traffic regulation by adenosine and protein kinase C. Neuron 38:417–432

    PubMed  CAS  Google Scholar 

  121. Light PE, Bladen C, Winkfein RJ, Walsh MP, French RJ (2000) Molecular basis of protein kinase C-induced activation of ATP-sensitive potassium channels. Proc Natl Acad Sci USA 97:9058–9063

    PubMed  CAS  PubMed Central  Google Scholar 

  122. Dorschner H, Brekardin E, Uhde I, Schwanstecher C, Schwanstecher M (1999) Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure. Mol Pharmacol 55:1060–1066

    PubMed  CAS  Google Scholar 

  123. Rorsman P, Renstrom E (2003) Insulin granule dynamics in pancreatic beta cells. Diabetologia 46:1029–1045

    PubMed  CAS  Google Scholar 

  124. Satin LS (2000) Localized calcium influx in pancreatic β-cells: its significance for Ca2+-dependent insulin secretion from the islets of Langerhans. Endocrine 13:251–262

    PubMed  CAS  Google Scholar 

  125. Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16:521–555

    PubMed  CAS  Google Scholar 

  126. Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3:a003947

    PubMed  PubMed Central  Google Scholar 

  127. Catterall WA (1991) Functional subunit structure of voltage-gated calcium channels. Science 253:1499–1500

    PubMed  CAS  Google Scholar 

  128. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005) International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev 57:411–425

    PubMed  CAS  Google Scholar 

  129. Catterall WA, Striessnig J, Snutch TP, Perez-Reyes E (2003) International Union of Pharmacology. XL. Compendium of voltage-gated ion channels: calcium channels. Pharmacol Rev 55:579–581

    PubMed  CAS  Google Scholar 

  130. Takahashi M, Seagar MJ, Jones JF, Reber BF, Catterall WA (1987) Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proc Natl Acad Sci USA 84:5478–5482

    PubMed  CAS  PubMed Central  Google Scholar 

  131. Rorsman P, Braun M, Zhang Q (2012) Regulation of calcium in pancreatic α- and β-cells in health and disease. Cell Calcium 51:300–308

    PubMed  CAS  PubMed Central  Google Scholar 

  132. Wang MC, Collins RF, Ford RC, Berrow NS, Dolphin AC, Kitmitto A (2004) The three-dimensional structure of the cardiac L-type voltage-gated calcium channel: comparison with the skeletal muscle form reveals a common architectural motif. J Biol Chem 279:7159–7168

    PubMed  CAS  Google Scholar 

  133. Tang L, Gamal El-Din TM, Payandeh J, Martinez GQ, Heard TM, Scheuer T, Zheng N, Catterall WA (2014) Structural basis for Ca2+ selectivity of a voltage-gated calcium channel. Nature 505:56–61

    PubMed  Google Scholar 

  134. Van Petegem F, Clark KA, Chatelain FC, Minor DL Jr (2004) Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain. Nature 429:671–675

    PubMed  PubMed Central  Google Scholar 

  135. Chen YH, Li MH, Zhang Y, He LL, Yamada Y, Fitzmaurice A, Shen Y, Zhang H, Tong L, Yang J (2004) Structural basis of the α1-β subunit interaction of voltage-gated Ca2+ channels. Nature 429:675–680

    PubMed  CAS  Google Scholar 

  136. Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, Obermuller S, Olofsson CS, Salehi A, Wendt A, Klugbauer N, Wollheim CB, Rorsman P, Hofmann F (2003) Impaired insulin secretion and glucose tolerance in β cell-selective CaV1.2 Ca2+ channel null mice. EMBO J 22:3844–3854

    PubMed  CAS  PubMed Central  Google Scholar 

  137. Rorsman P, Trube G (1986) Calcium and delayed potassium currents in mouse pancreatic β-cells under voltage-clamp conditions. J Physiol 374:531–550

    PubMed  CAS  PubMed Central  Google Scholar 

  138. Hofmann F, Flockerzi V, Kahl S, Wegener JW (2014) L-type CaV1.2 calcium channels: from in vitro findings to in vivo function. Physiol Rev 94:303–326

    PubMed  CAS  Google Scholar 

  139. Jing X, Li DQ, Olofsson CS, Salehi A, Surve VV, Caballero J, Ivarsson R, Lundquist I, Pereverzev A, Schneider T, Rorsman P, Renstrom E (2005) CaV2.3 calcium channels control second-phase insulin release. J Clin Invest 115:146–154

    PubMed  CAS  PubMed Central  Google Scholar 

  140. Eliasson L, Abdulkader F, Braun M, Galvanovskis J, Hoppa MB, Rorsman P (2008) Novel aspects of the molecular mechanisms controlling insulin secretion. J Physiol 586:3313–3324

    PubMed  CAS  PubMed Central  Google Scholar 

  141. Bhattacharjee A, Whitehurst RM Jr, Zhang M, Wang L, Li M (1997) T-type calcium channels facilitate insulin secretion by enhancing general excitability in the insulin-secreting β-cell line, INS-1. Endocrinology 138:3735–3740

    PubMed  CAS  Google Scholar 

  142. Ohta M, Nelson J, Nelson D, Meglasson MD, Erecinska M (1993) Effect of Ca++ channel blockers on energy level and stimulated insulin secretion in isolated rat islets of Langerhans. J Pharmacol Exp Ther 264:35–40

    PubMed  CAS  Google Scholar 

  143. Kanno T, Suga S, Wu J, Kimura M, Wakui M (1998) Intracellular cAMP potentiates voltage-dependent activation of L-type Ca2+ channels in rat islet β-cells. Pflugers Arch 435:578–580

    PubMed  CAS  Google Scholar 

  144. Henquin JC, Meissner HP (1983) Dibutyryl cyclic AMP triggers Ca2+ influx and Ca2+-dependent electrical activity in pancreatic B cells. Biochem Biophys Res Commun 112:614–620

    PubMed  CAS  Google Scholar 

  145. Gillis KD, Misler S (1993) Enhancers of cytosolic cAMP augment depolarization-induced exocytosis from pancreatic B-cells: evidence for effects distal to Ca2+ entry. Pflugers Arch 424:195–197

    PubMed  CAS  Google Scholar 

  146. Ammala C, Ashcroft FM, Rorsman P (1993) Calcium-independent potentiation of insulin release by cyclic AMP in single β-cells. Nature 363:356–358

    PubMed  CAS  Google Scholar 

  147. Love JA, Richards NW, Owyang C, Dawson DC (1998) Muscarinic modulation of voltage-dependent Ca2+ channels in insulin-secreting HIT-T15 cells. Am J Physiol 274:G397–G405

    PubMed  CAS  Google Scholar 

  148. Arkhammar P, Juntti-Berggren L, Larsson O, Welsh M, Nanberg E, Sjoholm A, Kohler M, Berggren PO (1994) Protein kinase C modulates the insulin secretory process by maintaining a proper function of the β-cell voltage-activated Ca2+ channels. J Biol Chem 269:2743–2749

    PubMed  CAS  Google Scholar 

  149. Platano D, Pollo A, Carbone E, Aicardi G (1996) Up-regulation of L- and non-L, non-N-type Ca2+ channels by basal and stimulated protein kinase C activation in insulin-secreting RINm5F cells. FEBS Lett 391:189–194

    PubMed  CAS  Google Scholar 

  150. Ishikawa T, Kaneko Y, Sugino F, Nakayama K (2003) Two distinct effects of cGMP on cytosolic Ca2+ concentration of rat pancreatic β-cells. J Pharmacol Sci 91:41–46

    PubMed  CAS  Google Scholar 

  151. Doerner D, Alger BE (1988) Cyclic GMP depresses hippocampal Ca2+ current through a mechanism independent of cGMP-dependent protein kinase. Neuron 1:693–699

    PubMed  CAS  Google Scholar 

  152. Li G, Hidaka H, Wollheim CB (1992) Inhibition of voltage-gated Ca2+ channels and insulin secretion in HIT cells by the Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62: comparison with antagonists of calmodulin and L-type Ca2+ channels. Mol Pharmacol 42:489–498

    PubMed  CAS  Google Scholar 

  153. Bhatt HS, Conner BP, Prasanna G, Yorio T, Easom RA (2000) Dependence of insulin secretion from permeabilized pancreatic β-cells on the activation of Ca2+/calmodulin-dependent protein kinase II. A re-evaluation of inhibitor studies. Biochem Pharmacol 60:1655–1663

    PubMed  CAS  Google Scholar 

  154. Ammala C, Eliasson L, Bokvist K, Berggren PO, Honkanen RE, Sjoholm A, Rorsman P (1994) Activation of protein kinases and inhibition of protein phosphatases play a central role in the regulation of exocytosis in mouse pancreatic β cells. Proc Natl Acad Sci USA 91:4343–4347

    PubMed  CAS  PubMed Central  Google Scholar 

  155. Rosenbaum T, Castanares DT, Lopez-Vaides HE, Hiriart M (2002) Nerve growth factor increases L-type calcium current in pancreatic β cells in culture. J Membr Biol 186:177–184

    PubMed  CAS  Google Scholar 

  156. Rosenbaum T, Sanchez-Soto MC, Hiriart M (2001) Nerve growth factor increases insulin secretion and barium current in pancreatic β-cells. Diabetes 50:1755–1762

    PubMed  CAS  Google Scholar 

  157. Blair LA, Marshall J (1997) IGF-1 modulates N and L calcium channels in a PI 3-kinase-dependent manner. Neuron 19:421–429

    PubMed  CAS  Google Scholar 

  158. Roper MG, Qian WJ, Zhang BB, Kulkarni RN, Kahn CR, Kennedy RT (2002) Effect of the insulin mimetic L-783,281 on intracellular Ca2+ and insulin secretion from pancreatic β-cells. Diabetes 51:S43–S49

    PubMed  CAS  Google Scholar 

  159. Brubaker PL, Drucker DJ (2002) Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Receptors Channels 8:179–188

    PubMed  CAS  Google Scholar 

  160. Britsch S, Krippeit-Drews P, Lang F, Gregor M, Drews G (1995) Glucagon-like peptide-1 modulates Ca2+ current but not K+ ATP current in intact mouse pancreatic B-cells. Biochem Biophys Res Commun 207:33–39

    PubMed  CAS  Google Scholar 

  161. Suga S, Kanno T, Nakano K, Takeo T, Dobashi Y, Wakui M (1997) GLP-I(7-36) amide augments Ba2+ current through L-type Ca2+ channel of rat pancreatic β-cell in a cAMP-dependent manner. Diabetes 46:1755–1760

    PubMed  CAS  Google Scholar 

  162. Gilon P, Yakel J, Gromada J, Zhu Y, Henquin JC, Rorsman P (1997) G protein-dependent inhibition of L-type Ca2+ currents by acetylcholine in mouse pancreatic B-cells. J Physiol 499:65–76

    PubMed  CAS  PubMed Central  Google Scholar 

  163. Gromada J, Bokvist K, Ding WG, Holst JJ, Nielsen JH, Rorsman P (1998) Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in human pancreatic β-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes 47:57–65

    PubMed  CAS  Google Scholar 

  164. Gromada J, Brock B, Schmitz O, Rorsman P (2004) Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential. Basic Clin Pharmacol Toxicol 95:252–262

    PubMed  CAS  Google Scholar 

  165. Gromada J, Holst JJ, Rorsman P (1998) Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflugers Arch 435:583–594

    PubMed  CAS  Google Scholar 

  166. Salapatek AMF, MacDonald PE, Gaisano HY, Wheeler MB (1999) Mutations to the third cytoplasmic domain of the glucagon-like peptide 1 (GLP-1) receptor can functionally uncouple GLP-1-stimulated insulin secretion in HIT-T15 cells. Mol Endocrinol 13:1305–1317

    PubMed  CAS  Google Scholar 

  167. Hsu WH, Xiang HD, Rajan AS, Boyd AE 3rd (1991) Activation of α2-adrenergic receptors decreases Ca2+ influx to inhibit insulin secretion in a hamster β-cell line: an action mediated by a guanosine triphosphate-binding protein. Endocrinology 128:958–964

    PubMed  CAS  Google Scholar 

  168. Hsu WH, Xiang HD, Rajan AS, Kunze DL, Boyd AE 3rd (1991) Somatostatin inhibits insulin secretion by a G-protein-mediated decrease in Ca2+ entry through voltage-dependent Ca2+ channels in the β cell. J Biol Chem 266:837–843

    PubMed  CAS  Google Scholar 

  169. Degtiar VE, Harhammer R, Nurnberg B (1997) Receptors couple to L-type calcium channels via distinct Go proteins in rat neuroendocrine cell lines. J Physiol 502:321–333

    PubMed  CAS  PubMed Central  Google Scholar 

  170. Nilsson T, Arkhammar P, Rorsman P, Berggren PO (1989) Suppression of insulin release by galanin and somatostatin is mediated by a G-protein. An effect involving repolarization and reduction in cytoplasmic free Ca2+ concentration. J Biol Chem 264:973–980

    PubMed  CAS  Google Scholar 

  171. Rorsman P, Arkhammar P, Berggren PO, Nilsson T (1987) Clonidine inhibition of glucoe-stimulated insulin-release involves reduction of the Ca2+ current. Diabetologia 30:A575

    Google Scholar 

  172. Keahey HH, Boyd AE 3rd, Kunze DL (1989) Catecholamine modulation of calcium currents in clonal pancreatic β-cells. Am J Physiol 257:C1171–C1176

    PubMed  CAS  Google Scholar 

  173. Bokvist K, Ammala C, Berggren PO, Rorsman P, Wahlander K (1991) Alpha2-adrenoreceptor stimulation does not inhibit L-type calcium channels in mouse pancreatic β-cells. Biosci Rep 11:147–157

    PubMed  CAS  Google Scholar 

  174. Rorsman P, Bokvist K, Ammala C, Arkhammar P, Berggren PO, Larsson O, Wahlander K (1991) Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic B cells. Nature 349:77–79

    PubMed  CAS  Google Scholar 

  175. Homaidan FR, Sharp GW, Nowak LM (1991) Galanin inhibits a dihydropyridine-sensitive Ca2+ current in the RINm5f cell line. Proc Natl Acad Sci USA 88:8744–8748

    PubMed  CAS  PubMed Central  Google Scholar 

  176. Yoshikawa H, Hellstrom-Lindahl E, Grill V (2005) Evidence for functional nicotinic receptors on pancreatic β cells. Metabolism 54:247–254

    PubMed  CAS  Google Scholar 

  177. Yaney GC, Wheeler MB, Wei X, Perez-Reyes E, Birnbaumer L, Boyd AE 3rd, Moss LG (1992) Cloning of a novel α1-subunit of the voltage-dependent calcium channel from the β-cell. Mol Endocrinol 6:2143–2152

    PubMed  CAS  Google Scholar 

  178. Wiser O, Trus M, Hernandez A, Renstrom E, Barg S, Rorsman P, Atlas D (1999) The voltage sensitive LC-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci USA 96:248–253

    PubMed  CAS  PubMed Central  Google Scholar 

  179. Yang SN, Larsson O, Branstrom R, Bertorello AM, Leibiger B, Leibiger IB, Moede T, Kohler M, Meister B, Berggren PO (1999) Syntaxin 1 interacts with the LD subtype of voltage-gated Ca2+ channels in pancreatic β cells. Proc Natl Acad Sci USA 96:10164–10169

    PubMed  CAS  PubMed Central  Google Scholar 

  180. Ji J, Yang SN, Huang X, Li X, Sheu L, Diamant N, Berggren PO, Gaisano HY (2002) Modulation of L-type Ca2+ channels by distinct domains within SNAP-25. Diabetes 51:1425–1436

    PubMed  CAS  Google Scholar 

  181. Atlas D (2014) Voltage-gated calcium channels function as Ca2+-activated signaling receptors. Trends Biochem Sci 39:45–52

    PubMed  CAS  Google Scholar 

  182. Trus M, Corkey RF, Nesher R, Richard AM, Deeney JT, Corkey BE, Atlas D (2007) The L-type voltage-gated Ca2+ channel is the Ca2+ sensor protein of stimulus-secretion coupling in pancreatic beta cells. Biochemistry 46:14461–14467

    PubMed  CAS  Google Scholar 

  183. Smith PA, Rorsman P, Ashcroft FM (1989) Modulation of dihydropyridine-sensitive Ca2+ channels by glucose metabolism in mouse pancreatic β-cells. Nature 342:550–553

    PubMed  CAS  Google Scholar 

  184. Iwashima Y, Pugh W, Depaoli AM, Takeda J, Seino S, Bell GI, Polonsky KS (1993) Expression of calcium channel mRNAs in rat pancreatic islets and downregulation after glucose infusion. Diabetes 42:948–955

    PubMed  CAS  Google Scholar 

  185. Iwashima Y, Kondoh-Abiko A, Seino S, Takeda J, Eto M, Polonsky KS, Makino I (1994) Reduced levels of messenger ribonucleic acid for calcium channel, glucose transporter-2, and glucokinase are associated with alterations in insulin secretion in fasted rats. Endocrinology 135:1010–1017

    PubMed  CAS  Google Scholar 

  186. Fukuda M, Mikoshiba K (1997) The function of inositol high polyphosphate binding proteins. BioEssays 19:593–603

    PubMed  CAS  Google Scholar 

  187. Tsui MM, York JD (2010) Roles of inositol phosphates and inositol pyrophosphates in development, cell signaling and nuclear processes. Adv Enzyme Regul 50:324–337

    PubMed  PubMed Central  Google Scholar 

  188. Montpetit B, Thomsen ND, Helmke KJ, Seeliger MA, Berger JM, Weis K (2011) A conserved mechanism of DEAD-box ATPase activation by nucleoporins and InsP6 in mRNA export. Nature 472:238–242

    PubMed  CAS  PubMed Central  Google Scholar 

  189. Larsson O, Barker CJ, Sjoholm A, Carlqvist H, Michell RH, Bertorello A, Nilsson T, Honkanen RE, Mayr GW, Zwiller J, Berggren PO (1997) Inhibition of phosphatases and increased Ca2+ channel activity by inositol hexakisphosphate. Science 278:471–474

    PubMed  CAS  Google Scholar 

  190. Hoy M, Efanov AM, Bertorello AM, Zaitsev SV, Olsen HL, Bokvist K, Leibiger B, Leibiger IB, Zwiller J, Berggren PO, Gromada J (2002) Inositol hexakisphosphate promotes dynamin I-mediated endocytosis. Proc Natl Acad Sci USA 99:6773–6777

    PubMed  CAS  PubMed Central  Google Scholar 

  191. Hoy M, Berggren PO, Gromada J (2003) Involvement of protein kinase C-ε in inositol hexakisphosphate-induced exocytosis in mouse pancreatic β-cells. J Biol Chem 278:35168–35171

    PubMed  CAS  Google Scholar 

  192. Efanov AM, Zaitsev SV, Berggren PO (1997) Inositol hexakisphosphate stimulates non-Ca2+-mediated and primes Ca2+-mediated exocytosis of insulin by activation of protein kinase C. Proc Natl Acad Sci USA 94:4435–4439

    PubMed  CAS  PubMed Central  Google Scholar 

  193. Yang SN, Shi Y, Yang G, Li Y, Yu L, Shin OH, Bacaj T, Sudhof TC, Yu J, Berggren PO (2012) Inositol hexakisphosphate suppresses excitatory neurotransmission via synaptotagmin-1 C2B domain in the hippocampal neuron. Proc Natl Acad Sci USA 109:12183–12188

    PubMed  CAS  PubMed Central  Google Scholar 

  194. Yang SN, Yu J, Mayr GW, Hofmann F, Larsson O, Berggren PO (2001) Inositol hexakisphosphate increases L-type Ca2+ channel activity by stimulation of adenylyl cyclase. FASEB J 15:1753–1763

    PubMed  CAS  Google Scholar 

  195. Yu J, Leibiger B, Yang SN, Caffery JJ, Shears SB, Leibiger IB, Barker CJ, Berggren PO (2003) Cytosolic multiple inositol polyphosphate phosphatase in the regulation of cytoplasmic free Ca2+ concentration. J Biol Chem 278:46210–46218

    PubMed  CAS  Google Scholar 

  196. Refai E, Dekki N, Yang SN, Imreh G, Cabrera O, Yu L, Yang G, Norgren S, Rossner SM, Inverardi L, Ricordi C, Olivecrona G, Andersson M, Jornvall H, Berggren PO, Juntti-Berggren L (2005) Transthyretin constitutes a functional component in pancreatic β-cell stimulus-secretion coupling. Proc Natl Acad Sci USA 102:17020–17025

    PubMed  CAS  PubMed Central  Google Scholar 

  197. Olofsson CS, Salehi A, Holm C, Rorsman P (2004) Palmitate increases L-type Ca2+ currents and the size of the readily releasable granule pool in mouse pancreatic β-cells. J Physiol 557:935–948

    PubMed  CAS  PubMed Central  Google Scholar 

  198. Lee AK, Yeung-Yam-Wah V, Tse FW, Tse A (2011) Cholesterol elevation impairs glucose-stimulated Ca2+ signaling in mouse pancreatic β-cells. Endocrinology 152:3351–3361

    PubMed  CAS  Google Scholar 

  199. Xia F, Xie L, Mihic A, Gao X, Chen Y, Gaisano HY, Tsushima RG (2008) Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic β-cells. Endocrinology 149:5136–5145

    PubMed  CAS  Google Scholar 

  200. Berggren PO, Larsson O (1994) Ca2+ and pancreatic β-cell function. Biochem Soc Trans 22:12–18

    PubMed  CAS  Google Scholar 

  201. Namkung Y, Skrypnyk N, Jeong MJ, Lee T, Lee MS, Kim HL, Chin H, Suh PG, Kim SS, Shin HS (2001) Requirement for the L-type Ca2+ channel α1D subunit in postnatal pancreatic β cell generation. J Clin Invest 108:1015–1022

    PubMed  CAS  PubMed Central  Google Scholar 

  202. Sjoholm A (1995) Regulation of insulinoma cell proliferation and insulin accumulation by peptides and second messengers. Ups J Med Sci 100:201–216

    PubMed  CAS  Google Scholar 

  203. Popiela H, Moore W (1991) Tolbutamide stimulates proliferation of pancreatic β cells in culture. Pancreas 6:464–469

    PubMed  CAS  Google Scholar 

  204. German MS, Moss LG, Rutter WJ (1990) Regulation of insulin gene expression by glucose and calcium in transfected primary islet cultures. J Biol Chem 265:22063–22066

    PubMed  CAS  Google Scholar 

  205. Efrat S, Surana M, Fleischer N (1991) Glucose induces insulin gene transcription in a murine pancreatic β-cell line. J Biol Chem 266:11141–11143

    PubMed  CAS  Google Scholar 

  206. Macfarlane WM, Campbell SC, Elrick LJ, Oates V, Bermano G, Lindley KJ, Aynsley-Green A, Dunne MJ, James RF, Docherty K (2000) Glucose regulates islet amyloid polypeptide gene transcription in a PDX1- and calcium-dependent manner. J Biol Chem 275:15330–15335

    PubMed  CAS  Google Scholar 

  207. Lee B, Laychock SG (2000) Regulation of inositol trisphosphate receptor isoform expression in glucose-desensitized rat pancreatic islets: role of cyclic adenosine 3′,5′-monophosphate and calcium. Endocrinology 141:1394–1402

    PubMed  CAS  Google Scholar 

  208. Huo J, Metz SA, Li G (2003) Role of tissue transglutaminase in GTP depletion-induced apoptosis of insulin-secreting (HIT-T15) cells. Biochem Pharmacol 66:213–223

    PubMed  CAS  Google Scholar 

  209. Efanova IB, Zaitsev SV, Zhivotovsky B, Kohler M, Efendic S, Orrenius S, Berggren PO (1998) Glucose and tolbutamide induce apoptosis in pancreatic β-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem 273:33501–33507

    PubMed  CAS  Google Scholar 

  210. Chang I, Cho N, Kim S, Kim JY, Kim E, Woo JE, Nam JH, Kim SJ, Lee MS (2004) Role of calcium in pancreatic islet cell death by IFN-γ/TNF-α. J Immunol 172:7008–7014

    PubMed  CAS  Google Scholar 

  211. Zaitsev SV, Appelskog IB, Kapelioukh IL, Yang SN, Kohler M, Efendic S, Berggren PO (2001) Imidazoline compounds protect against interleukin 1β-induced β-cell apoptosis. Diabetes 50:S70–S76

    PubMed  CAS  Google Scholar 

  212. Shi Y, Yang G, Yu J, Yu L, Westenbroek R, Catterall WA, Juntti-Berggren L, Berggren PO, Yang SN (2014) Apolipoprotein CIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src. Cell Mol Life Sci 71:1289–1303

    PubMed  CAS  Google Scholar 

  213. Dekki N, Nilsson R, Norgren S, Rossner SM, Appelskog I, Marcus C, Simell O, Pugliese A, Alejandro R, Ricordi C, Berggren PO, Juntti-Berggren L (2007) Type 1 diabetic serum interferes with pancreatic β-cell Ca2+-handling. Biosci Rep 27:321–326

    PubMed  CAS  Google Scholar 

  214. Holmberg R, Refai E, Höög A, Crooke RM, Graham M, Olivecrona G, Berggren PO, Juntti-Berggren L (2011) Lowering apolipoprotein CIII delays onset of type 1 diabetes. Proc Natl Acad Sci USA 108:10685–10689

    PubMed  CAS  PubMed Central  Google Scholar 

  215. Juntti-Berggren L, Refai E, Appelskog I, Andersson M, Imreh G, Dekki N, Uhles S, Yu L, Griffiths WJ, Zaitsev S, Leibiger I, Yang SN, Olivecrona G, Jornvall H, Berggren PO (2004) Apolipoprotein CIII promotes Ca2+-dependent β cell death in type 1 diabetes. Proc Natl Acad Sci USA 101:10090–10094

    PubMed  CAS  PubMed Central  Google Scholar 

  216. Juntti-Berggren L, Larsson O, Rorsman P, Ammala C, Bokvist K, Wahlander K, Nicotera P, Dypbukt J, Orrenius S, Hallberg A, Berggren PO (1993) Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes. Science 261:86–90

    PubMed  CAS  Google Scholar 

  217. Chandra J, Yang SN, Kohler M, Zaitsev S, Juntti-Berggren L, Berggren PO, Zhivotovsky B, Orrenius S (2001) Effects of serum from patients with type 1 diabetes on primary cerebellar granule cells. Diabetes 50:S77–S81

    PubMed  CAS  Google Scholar 

  218. Adair B, Nunn R, Lewis S, Dukes I, Philipson L, Yeager M (2008) Single particle image reconstruction of the human recombinant Kv2.1 channel. Biophys J 94:2106–2114

    PubMed  CAS  PubMed Central  Google Scholar 

  219. Mohapatra DP, Siino DF, Trimmer JS (2008) Interdomain cytoplasmic interactions govern the intracellular trafficking, gating, and modulation of the Kv2.1 channel. J Neurosci 28:4982–4994

    PubMed  CAS  PubMed Central  Google Scholar 

  220. Pfaffinger PJ, DeRubeis D (1995) Shaker K+ channel T1 domain self-tetramerizes to a stable structure. J Biol Chem 270:28595–28600

    PubMed  CAS  Google Scholar 

  221. Kreusch A, Pfaffinger PJ, Stevens CF, Choe S (1998) Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392:945–948

    PubMed  CAS  Google Scholar 

  222. Bixby KA, Nanao MH, Shen NV, Kreusch A, Bellamy H, Pfaffinger PJ, Choe S (1999) Zn2+-binding and molecular determinants of tetramerization in voltage-gated K+ channels. Nat Struct Biol 6:38–43

    PubMed  CAS  Google Scholar 

  223. Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R (2002) The open pore conformation of potassium channels. Nature 417:523–526

    PubMed  CAS  Google Scholar 

  224. Long SB, Campbell EB, Mackinnon R (2005) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309:897–903

    PubMed  CAS  Google Scholar 

  225. Smith PA, Bokvist K, Arkhammar P, Berggren PO, Rorsman P (1990) Delayed rectifying and calcium-activated K+ channels and their significance for action potential repolarization in mouse pancreatic β-cells. J Gen Physiol 95:1041–1059

    PubMed  CAS  Google Scholar 

  226. Mohapatra DP, Park KS, Trimmer JS (2007) Dynamic regulation of the voltage-gated Kv2.1 potassium channel by multisite phosphorylation. Biochem Soc Trans 35:1064–1068

    PubMed  CAS  Google Scholar 

  227. MacDonald PE, Salapatek AM, Wheeler MB (2003) Temperature and redox state dependence of native Kv2.1 currents in rat pancreatic β-cells. J Physiol 546:647–653

    PubMed  CAS  PubMed Central  Google Scholar 

  228. Bao S, Jacobson DA, Wohltmann M, Bohrer A, Jin W, Philipson LH, Turk J (2008) Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA2β in pancreatic β-cells and in iPLA2β-null mice. Am J Physiol Endocrinol Metab 294:E217–E229

    PubMed  CAS  PubMed Central  Google Scholar 

  229. Long SB, Tao X, Campbell EB, MacKinnon R (2007) Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450:376–382

    PubMed  CAS  Google Scholar 

  230. Schmidt D, Jiang QX, MacKinnon R (2006) Phospholipids and the origin of cationic gating charges in voltage sensors. Nature 444:775–779

    PubMed  CAS  Google Scholar 

  231. Xia F, Gao X, Kwan E, Lam PP, Chan L, Sy K, Sheu L, Wheeler MB, Gaisano HY, Tsushima RG (2004) Disruption of pancreatic β-cell lipid rafts modifies Kv2.1 channel gating and insulin exocytosis. J Biol Chem 279:24685–24691

    PubMed  CAS  Google Scholar 

  232. MacDonald PE, Salapatek AM, Wheeler MB (2002) Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K+ currents in β-cells: a possible glucose-dependent insulinotropic mechanism. Diabetes 51:S443–S447

    PubMed  CAS  Google Scholar 

  233. Feng DD, Luo Z, Roh SG, Hernandez M, Tawadros N, Keating DJ, Chen C (2006) Reduction in voltage-gated K+ currents in primary cultured rat pancreatic β-cells by linoleic acids. Endocrinology 147:674–682

    PubMed  CAS  Google Scholar 

  234. Jacobson DA, Weber CR, Bao S, Turk J, Philipson LH (2007) Modulation of the pancreatic islet β-cell-delayed rectifier potassium channel Kv2.1 by the polyunsaturated fatty acid arachidonate. J Biol Chem 282:7442–7449

    PubMed  CAS  PubMed Central  Google Scholar 

  235. Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG (2000) Targeted overactivity of β cell KATP channels induces profound neonatal diabetes. Cell 100:645–654

    PubMed  CAS  Google Scholar 

  236. Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the β cell: the last ten years. Cell 148:1160–1171

    PubMed  CAS  Google Scholar 

  237. Speier S, Nyqvist D, Cabrera O, Yu J, Molano RD, Pileggi A, Moede T, Kohler M, Wilbertz J, Leibiger B, Ricordi C, Leibiger IB, Caicedo A, Berggren PO (2008) Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med 14:574–578

    PubMed  CAS  PubMed Central  Google Scholar 

  238. Speier S, Nyqvist D, Kohler M, Caicedo A, Leibiger IB, Berggren PO (2008) Noninvasive high-resolution in vivo imaging of cell biology in the anterior chamber of the mouse eye. Nat Protoc 3:1278–1286

    PubMed  CAS  PubMed Central  Google Scholar 

  239. Walker JN, Ramracheya R, Zhang Q, Johnson PR, Braun M, Rorsman P (2011) Regulation of glucagon secretion by glucose: paracrine, intrinsic or both? Diabetes Obes Metab 13(Suppl 1):95–105

    PubMed  CAS  Google Scholar 

  240. Henquin JC, Nenquin M, Stiernet P, Ahren B (2006) In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse: pattern and role of cytoplasmic Ca2+ and amplification signals in β-cells. Diabetes 55:441–451

    PubMed  CAS  Google Scholar 

  241. Henquin JC, Dufrane D, Nenquin M (2006) Nutrient control of insulin secretion in isolated normal human islets. Diabetes 55:3470–3477

    PubMed  CAS  Google Scholar 

  242. Falke LC, Gillis KD, Pressel DM, Misler S (1989) ‘Perforated patch recording’ allows long-term monitoring of metabolite-induced electrical activity and voltage-dependent Ca2+ currents in pancreatic islet B cells. FEBS Lett 251:167–172

    PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shao-Nian Yang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, SN., Shi, Y., Yang, G. et al. Ionic mechanisms in pancreatic β cell signaling. Cell. Mol. Life Sci. 71, 4149–4177 (2014). https://doi.org/10.1007/s00018-014-1680-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-014-1680-6

Keywords

Navigation