Electrophysiology of pancreatic beta cells: a comprehensive review of ion channel function, electrical activity, and secretory mechanisms

Abstract

Pancreatic β-cells play a crucial role in maintaining glucose homeostasis through the regulation of insulin secre- tion. The electrophysiological properties of these cells, including ion channel function, electrical activity, and secretory mechanisms, are essential for their proper physiological function. In this comprehensive review, we provide an in-depth analysis of the electrophysiology of pancreatic β-cells. We discuss the various ion channels involved in the generation and modulation of electrical signals, such as voltage-gated ion channels, ATP-sensitive and delayed rectifier potassium ion channels, calcium ion channels, chloride channels and transient receptor poten- tial channels. Additionally, we examine the intricate interplay between intracellular calcium dynamics and insulin release. Furthermore, we explore the physiological and pathological factors that influence the electrophysiology of β-cells. A comprehensive understanding of the electrophysiological mechanisms governing pancreatic beta cell function is crucial for elucidating the pathogenesis of diabetes mellitus and developing novel therapeutic strategies.

Keywords

• pancreatic beta cell
• insulin
• electrophysiology
• KATP channels
• BK channels
• TRPM channels

Pankreas Beta Hücrelerinin Elektrofizyolojisi: İyon Kanal Fonksiyonları, Elektriksel Aktivite ve Sekresyon Mekanizmalarının Kapsamlı Bir Derlemesi

Abstract

Pankreatik β-hücreler, insülin salınımının düzenlenmesi yoluyla glukoz homeostazının korunmasında hayati bir rol oynar. Bu hücrelerin iyon kanalı fonksiyonu, elektriksel aktivite ve sekresyon mekanizmaları gibi elektrofizyolojik özellikleri, fizyolojik görevlerini sağlıklı bir şekilde yerine getirebilmeleri açısından kritik öneme sahiptir. Bu kapsamlı derlemede, pankreatik β-hücrelerin elektrofizyolojisi ayrıntılı olarak ele alınmaktadır. Elektriksel sinyal- lerin oluşumu ve modülasyonunda rol oynayan voltaj kapılı iyon kanalları, ATP'ye duyarlı ve gecikmeli rektifiye potasyum kanalları, kalsiyum iyon kanalları, klor kanalları ve geçici reseptör potansiyel (TRP) kanalları gibi çeşitli iyon kanalları tartışılmıştır. Ayrıca, hücre içi kalsiyum dinamiği ile insülin salınımı arasındaki karmaşık etkileşim incelenmiştir. Bunun yanı sıra, β-hücre elektrofizyolojisini etkileyen fizyolojik ve patolojik faktörler de gözden geçirilmiştir. Pankreatik beta hücre fonksiyonlarını yöneten elektrofizyolojik mekanizmaların kapsamlı bir şekilde anlaşılması, diyabetes mellitus patogenezinin aydınlatılması ve yeni tedavi stratejilerinin geliştirilmesi açısından büyük önem taşımaktadır.

Keywords

• pankreatik beta hücreleri
• insülin
• elektrofizyoloji
• KATP kanalları
• BK kanalları
• TRPM kanalları

References

1. 1. Meda P, Hanau D, Peers C, et al. Junctional communi- cation and the control of insulin secretion. J Cell Biol 1986;103(2):535-541.
2. 2.Rorsman P, Ashcroft FM. Pancreatic beta-cell electrical activity and insulin secretion: of mice and men. Physiol Rev 2018;98(1):117-214.
3. 3. Shimomura, K, Maejima Y. KATP Channel Mutations and Neonatal Diabetes. Internal medicine 2017; 56(18): 2387–2393. Doi:10.2169/internal medicine.8454-16
4. 4. Schulla V, Briant L, Salehi A, et al. Regulation of cal- cium channels in the pancreatic beta-cell. Adv Exp Med Biol 2003; 530:157-175.
5. 5. Dean PM, Matthews EK. Electrical activity in pancrea- tic islet cells. Nature 1986;219(5156):389-390.
6. 6. Ashcroft FM. ATP-sensitive potassium channelopat- hies: focus on insulin secretion. Diabetes 2005;54(9):2503–13
7. 7. Cook DL, Hales CN, Humphrey PP, et al. Oscillations in pancreatic islet membrane potentials. Proc Natl Acad Sci 1991;88(18):8472-8476.
8. 8. Kang H, Han K, Jo J, Kim J, Choi M. Systems of panc- reatic beta-cells and glucose regulation. Front Biosci 2008; 13:6421-6431.

9. 9. Braun M, Ramracheya R, Bengtsson M, et al. Voltage- gated ion channels in human pancreatic beta-cells: Elect- rophysiological characterization and role in insulin secre- tion. Diabetes 2008;57(6):1618-1628.
10. 10. Schulla V , Renstrom E, Feil R, et al. V oltage- dependent modulation of local Ca2+ release in dendrites of pyramidal neurons. J Physiol 2003;551(1):35-50.
11. 11. Barg S, Eliasson L, Renstrom E, et al. Delay between fusion pore opening and peptide release from large dense- core vesicles in neuroendocrine cells. Neuron 2001;29(1):231-242.
12. 12. Jing X, Li DQ, Olofsson CS, et al. Cav2.3 calcium channels control second-phase insulin release. J Clin Invest 2005;115(1):146-154.
13. 13. Jacobson DA, Kuznetsov A, Lopez JR, et al. Calcium- activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue-induced electrical responses. J Phy- siol Biochem 2010;66(4):325-336.
14. 14. Rorsman P, Trube G. Electrical activity and cytoplas- mic free calcium concentration in pancreatic beta-cells. Br J Pharmacol 1986;87(1):199-212.
15. 15. MacDonald PE, Braun M, Galvanovskis J, et al. Kv2.1 cell surface clusters are insertion platforms for ion channel delivery to the plasma membrane. Mol Pharmacol 2002;62(6):1413-1421.
16. 16. Ashcroft FM, Puljung MC, Vedovato N. Neonatal Diabetes and the KATP Channel: From Mutation to Therapy. Trends in endocrinology and metabolism: TEM 2017;28(5): 377–387. Doi: 10.1016/j.tem.2017.02.003
17. 17. Ciani SM, Ribalet B. Single ATP-sensitive K+ chan- nels in dialyzed and nucleated patches of rat ventricular myocytes. Biophys J 1988;54(6):1071-1080.
18. 18. Gillis KD, Mossner R, Henquin JC. Substrate-induced differences in the kinetic parameters of ATP-sensitive K+ channels from pancreatic B-cells. J Membr Biol 1989;111(3):239-249.
19. 19. Isenberg G, Daut J, Large WA. Burst-like behaviour of single Ca2+-activated K+ channels in myocytes from guinea-pig coronary artery. J Physiol 1988; 398:315-337. doi: 10.1113/jphysiol. 1988.sp017095.
20. 20. Rodríguez-Rivera NS, Barrera-Oviedo D. Exploring the Pathophysiology of ATP-Dependent Potassium Chan- nels in Insulin Resistance. International Journal of Mole- cular Sciences 2024;25(7):4079. https://doi.org/10.3390/ijms25074079
21. 21. Proks P. Neonatal diabetes caused by activating mutations in the sulphonylurea receptor. Diabetes Metab J 2013;37: 157-164.
22. 22. Masia R, De Leon DD, MacMullen C, McKnight H, Stanley CA, et al. A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neona- tal diabetes mellitus (PNDM). Diabetes 2007;56(5): 1357– 1362. Doi:10.2337/db06-1746
23. 23. de Wet H, Rees MG, Shimomura K, et al. Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neona- tal diabetes. Proceedings of the National Academy of Sciences of the United States of America 2007;104(48): 18988–18992. Doi:10.1073/pnas.0707428104
24. 24. Proks P, Lippiat J Membrane Ion Channels and Diabe- tes. Curr Pharm Des 2006;12(4):485-501.
25. 25. Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hype- rinsulinemic hypoglycemia of infancy. Science 1995;268(5209):426-429.
26. 26. MS Remedi, CG Nichols. KATP Channels in the Pancreas: Hyperinsulinism and Diabetes. In: Pitt GS (ed) Perspectives in Translational Cell Biology, Ion Channels in Health and Disease, 1st edn. Academic Press, Massachusetts, 2016; pp: 199-221, SBN 9780128020029. https://doi.org/10.1016/B978-0-12-802002-9.00008-X.
27. 27. Pinney SE, MacMullen C, Becker S, et al. Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. The Journal of clinical investigation 2008;118(8):2877–2886. https://doi.org/10.1172/JCI35414
28. 28. Zerangue N, Schwappach B, Jan YN, Jan LY. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron 1999;22(3):537-548.
29. 29. Okuyama Y, Fujiwara K, Kakei M, Nakamura M, Yanaihara N. Differential expression of sulfonylurea receptor subtypes in rat pancreatic islets. Mol Cell Endocrinol 1999;153(1-2):67-72.
30. 30. Ribalet B, John SA, Weiss JN. Regulation of ATP- sensitive K+ channels in intact ventricular myocytes: phosphorylation inhibits the activity of adenosine- sensitive K+ channels. Circ Res 1989;65(3):633-642.
31. 31. Lawson K, Downey JM. Modulation of ATP-sensitive K+ channels in vascular smooth muscle by protein kinase A. Am J Physiol 1993;265(4 Pt 2):H1619-H1625.
32. 32. Quayle JM, Nelson MT, Standen NB, et al. Properties and function of KATP in arterial smooth muscle. Am J Physiol 1994;266(3 Pt 1), C828-C836.
33. 33. Hatakeyama N, Suzuki S, Matsuda H, et al. Inhibition of ATP-sensitive potassium channels causes vasoconstriction through protein kinase C-dependent activation of the alpha 1-adrenoceptor in human cerebral arteries. Circ Res 1995;77(5), 897-902.
34. 34. Lin YW, Knaryan VH, Hwang PM, Chiang FT, Pao AC, Wu SN. Modulation of ATP-sensitive potassium channel Kir6.2 by the stimulatory GTP-binding protein. Mol Pharmacol 2003;63(4), 767-776.
35. 35. Lee KPK, Chen J, MacKinnon R. Molecular structure of human KATP in complex with ATP and ADP. Elife 2017;6:e32481. doi: 10.7554/eLife.32481
36. 36. Kakei M, Noma A, Shibasaki T. Membrane current through adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells. J Physiol 1986;379(1), 227-249.
37. 37. Akimbekov NS, Coban SO, Atfi A, Razzaque MS. The role of magnesium in pancreatic beta-cell function and homeostasis. Frontiers in nutrition 2024;11,1458700. doi: 10.3389/fnut.2024.1458700
38. 38. Abdulhadi-Atwan M, Bushman J, Tornovsky-Babaey S, et al. Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. Diabetes 2008;57(7): 1935– 1940. Doi:10.2337/db08-0159
39. 39. Flanagan SE, Clauin S, Bellanné-Chantelot C, et al. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Human mutation 2009;30(2), 170–180. Doi:10.1002/humu.20838
40. 40. Dunne MJ, Petersen OH. Intracellular Mg2+ and regulation of ATP-sensitive K+ channels in pancreatic acinar cells. Pflügers Archiv-European Journal of Physiology 1986;407(3):265-270.
41. 41. Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG. Targeted overactivity of beta cell KATP channels induces profound neonatal diabetes. Cell 2000;100: 645- 654
42. 42. Polak M, Cave H. Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis 2007; 2:12.
43. 43. Slingerland AS, Hattersley AT. Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes. J Clin Endocrinol Metab 2006;91(7):2782–8
44. 44. Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 2003;52(2): 568–572. Doi:10.2337/diabetes.52.2.568
45. 45. Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potas- sium-channel subunit Kir6.2 and permanent neonatal diabetes. The New England journal of medicine 2004;350(18): 1838–1849. Doi:10.1056/NEJMoa032922
46. 46. Kanakatti Shankar R, Pihoker C, Dolan LM, et al. Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for Diabetes in Youth Study. Pediatric diabetes 2013;14(3): 174–180. Doi:10.1111/pedi.12003
47. 47. Proks P, Girard C, Ashcroft FM. Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol Genet 2005;14(18):2717–26.
48. 48. Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S. Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neona- tal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes, obesity & metabolism 2007;9 Suppl 2(Suppl 2): 28–39. Doi:10.1111/j.1463-1326.2007. 00772.x
49. 49. Villareal DT, Koster JC, Robertson H, et al. 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 2009;58(8): 1869–1878. Doi:10.2337/db09-0025
50. 50. Rorsman P, Trube G, Atwater I. The pancreatic β-cell as a model system for the study of ion channels. Reviews of Physiology, Biochemistry and Pharmacology 1986;103:61-133.
51. 51. Kelly RP, Ashcroft SJ. Properties and metabolic regulation of the delayed rectifier potassium conductance in mouse pancreatic beta-cells. The Journal of Physiology 1990;421(1):93-110.
52. 52. Smith PA, Bokvist K, Rorsman P. Modulation of the delayed rectifier K+ current by external K+ and divalent cations in mouse pancreatic β-cells. The Journal of Physiology 1990;423(1):135-153.
53. 53. Becerra-Tomás N, Estruch R, Bulló M, et al. Increased serum calcium levels and risk of type 2 diabetes in individuals at high cardiovascular risk. Diabetes Care 2014;37(11):3084-3091
54. 54. Satin LS, Kinard TA, Smith PA. Multiple kinetic components of delayed rectifier K+ current in mouse pancreatic β-cells. Biophysical journal 1989;56(1):229- 241.
55. 55. Jacobson DA, Kuznetsov A, Lopez JP, Kash S, Am- mala CE, Philipson LH. Kv2.1 ablation alters glucose- induced islet electrical activity, enhancing insulin secretion. Cell Metab 2007;6(3):229-235.
56. 56. Jensen MV, Haldeman JM, Zhang H, et al. Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion. The Journal of biological chemistry 2013;288(32): 23128–23140. Doi:10.1074/jbc.M113.491654
57. 57. Bokvist K, Holmqvist M, Gromada J, Rorsman P, Weir GC, Efendic S. ATP-sensitive K+ channel- dependent depolarization of glucagon-producing α-cells by hyperglycemia. Diabetes 1990;39(9):897-902.
58. 58.WangJ,WangZ,YuJ,ZhangY,ZengY,GuZ.A forskolin-conjugated insulin analog targeting endogenous glucose-transporter for glucose-responsive insulin deli- very. Biomaterials Science 2019;7(11):4508-4513.
59. 59. Lubberding AF, Juhl CR, Skovhøj EZ, et al. Celebri- ties in the heart, strangers in the pancreatic beta cell: Vol- tage-gated potassium channels Kv 7.1 and Kv 11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes. Acta physiologica 2022;234(3), e13781. Doi:10.1111/apha.13781
60. 60. Herrington J, Zhou YP, Bugianesi RM, et al. Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion. Diabetes 2006;55(4): 1034–1042. Doi:10.2337/diabetes.55.04.06.db05-0788
61. 61. Kim SJ, Widenmaier SB, Choi WS, et al. Pancreatic β- cell prosurvival effects of the incretin hormones involve post-translational modification of Kv2.1 delayed rectifier channels. Cell death and differentiation 2012;19(2): 333– 344. Doi:10.1038/cdd.2011.102
62. 62. Kim S-J, Ao Z, Warnock G, McIntosh Christopher HS. Incretin- stimulated interaction between β-cell Kv1.5 and Kvβ2 chan- nel proteins involves acetyla- tion/deacetylation by CBP/SirT1. Biochem J 2013; 451(2):227-234.
63. 63. Yamagata K, Senokuchi T, Lu M, et al. Voltage-gated K+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line. Biochemical and biophysical research commu- nications 2011;407(3): 620–625. Doi:10.1016/j.bbrc.2011.03.083
64. 64. Lubberding AF, Zhang J, Lundh M, et al. Age- dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome LOF mutation Kcnq1-A340V. Scientific reports 2021;11(1): 12253. Doi:10.1038/s41598-021-90452-8
65. 65. Zhang J, Juhl CR, Hylten-Cavallius L, et al. Gain-of- function mutation in the voltage-gated potassium channel gene KCNQ1 and glucose-stimulated hypoinsulinemia - case report. BMC endocrine disorders 2020;20(1): 38. Doi:10.1186/s12902-020-0513-x
66. 66. Hyltén-Cavallius L, Iepsen EW, Wewer Albrechtsen NJ, et al. Patients with Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia. Circulation 2017;135(18): 1705–1719. Doi:10.1161/CIRCULATIONAHA.116.024279
67. 67. Cook DL, Ikeuchi M, Yasui K Whole-cell electrophysiological characterization of the calcium-activated potassium current in pancreatic β-cells. Pflügers Archiv European Journal of Physiology 1984;402(1):86-92.
68. 68. Düfer M, Neye Y, Hörth K, et al. BK channels affect glucose homeostasis and cell viability of murine pancreatic beta cells. Diabetologia 2011;54(2): 423–432. Doi:10.1007/s00125-010-1936-0
69. 69. Kukuljan M, Goncalves AA, Atwater I Charybdo- toxin-sensitive KCa channel is not involved in glucose- induced electrical activity in pancreatic beta-cells. J Membr Biol 1991; 119:187–195
70. 70. Haspel D, Krippeit-Drews P, Aguilar-Bryan L, et al. Crosstalk between membrane potential and cytosolic Ca2+ concentration in beta cells from Sur1−/− mice. Diabetolo- gia 2005; 48:913–921
71. 71. DiNicolantonio JJ, O'Keefe JH. Low-grade metabolic acidosis as a driver of insulin resistance. Open heart 2021;8(2):e001788. Doi:10.1136/openhrt-2021-001788
72. 72. Dickerson MT, Dadi PK, Altman MK, et al. Glucose- mediated inhibition of calcium-activated potassium channels limits α-cell calcium influx and glucagon secretion. American journal of physiology. Endocrinology and metabolism 2019;316(4):E646-E659. Doi:10.1152/ajpendo.00342.2018
73. 73. Tamarina NA, Wang Y, Mariotto L, et al. Small- conductance calcium-activated K+ channels are expressed in pancreatic islets and regulate glucose responses. Diabetes 2003;52(8):2000-2006. Doi:10.2337/diabetes.52.8.2000
74. 74. Düfer M, Gier B, Wolpers D, Krippeit-Drews P, Ruth P, Drews G. Enhanced glucose tolerance by SK4 channel inhibition in pancreatic beta-cells. Diabetes 2009;58(8):1835-43. Doi:10.2337/db08-1324
75. 75. Sehlin J. Interrelationship between chloride fluxes in pancreatic islets and insulin release. Am J Physiol 1978;4: E501–E508
76. 76. Lindström P, Norlund L, Sehlin J. Potassium and chloride fluxes are involved in volume regulation in mouse pancreatic islet cells. Acta Physiol Scand 1986; 128:541–546
77. 77. Kinard TA, Goforth, PB, Tao Q, et al. Chloride chan- nels regulate HIT cell volume but cannot fully account for swelling-induced insulin secretion. Diabetes 2001;50(5),992–1003. Doi:10.2337/diabetes.50.5.992
78. 78. Braun M, Wendt A, Birnir B, et al. Regulated exocyto- sis of GABA-containing synaptic-like microvesicles in pancreatic beta-cells. J Gen Physiol 2004; 123:191–204. Doi:/10.1085/jgp.200308966.
79. 79. Di Fulvio M, Aguilar-Bryan L. Chloride transporters and channels in β-cell physiology: revisiting a 40-year-old model. Biochemical Society transactions 2019;47(6): 1843–1855. Doi:10.1042/BST20190513
80. 80. Fujimoto W, Miki T, Ogura T, et al. Niflumic acid- sensitive ion channels play an important role in the induc- tion of glucose-stimulated insulin secretion by cyclic AMP in mice. Diabetologia 2009;52: 863–872. Doi:10.1007/s00125-009-1306-y
81. 81. Kang C, Xie L, Gunasekar SK, et al. SWELL1 is a glucose sensor regulating beta-cell excitability and syste- mic glycaemia. Nat Commun 2018; 9:367 Doi:10.1038/s41467-017-02664-0
82. 82. Best L, Brown PD, Sener A, Malaisse WJ. Electrical activity in pancreatic islet cells: the VRAC hypothesis. Islets 2010;2: 59–64. Doi:10.4161/isl.2.2.11171
83. 83. Stuhlmann T, Planells-Cases R, Jentsch TJ. LRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion. Nature communications 2018;9(1):1974. Doi:10.1038/s41467-018-04353-y
84. 84. Strange K, Yamada T, Denton JS. A 30-year journey from volume-regulated anion currents to molecular structure of the LRRC8 channel. The Journal of general physio- logy 2019;151(2):100–117. Doi:10.1085/jgp.201812138
85. 85. Guo JH, Chen H, Ruan YC, et al. Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR. Nat Commun 2014; 5:4420. Doi:10.1038/ncomms5420.
86. 86. Sun X, Yi Y, Xie W, et al. CFTR influences beta cell function and insulin secretion through non-cell autono- mous exocrine-derived factors. Endocrinology 2017; 158:3325–3338. Doi:10.1210/en.2017-00187
87. 87. Hart NJ, Aramandla R, Poffenberger G, et al. Cystic fibrosis-related diabetes is caused by islet loss and inf- lammation. JCI Insight 2018;3(8): e98240. Doi: 10.1172/jci.insight.98240
88. 88. Edlund A, Esguerra JL, Wendt A, Flodström-Tullberg M, Eliasson L. CFTR and Anoctamin 1 (ANO1) contribu- te to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells. BMC medicine 2014;12: 87. Doi:10.1186/1741-7015-12-87
89. 89. Edlund A, Barghouth M, Huhn M, et al. Defective exocytosis and processing of insulin in a cystic fibrosis mouse model. The Journal of endocrinology 2019; JOE- 18-0570.R1. Doi:10.1530/JOE-18-0570
90. 90. Kozak JA, Logothetis DE. A calcium-dependent chlo- ride current in insulin-secreting beta TC-3 cells. Pflugers Arch 1997; 433:679–690. Doi:10.1007/s004240050332
91. 91. Crutzen, R, Virreira M, Markadieu N, et al. Anoctamin 1 (Ano1) is required for glucose-induced membrane potential oscillations and insulin secretion by murine beta- cells. Pflugers Arch 2016; 468:573–591. Doi:10.1007/s00424-015-1758-5
92. 92. Jian X, Felsenfeld G. Insulin promoter in human panc- reatic beta cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism. Proc. Natl Acad. Sci. U.S.A 2018;115: E4633–E4641. Doi:10.1073/pnas.1803146115
93. 93. Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem 2007; 76:387–417. Doi: 10.1146/annurev.biochem.75.103004.142819.
94. 94. Colsoul B, Vennekens R, Nilius B. Transient receptor potential cation channels in pancreatic β cells. Rev Physiol Biochem Pharmacol 2011; 161:87–110. Doi:10.1007/112_2011_2.
95. 95. Sumoza-Toledo A, Penner R. TRPM2: a multifunctio- nal ion channel for calcium signalling. J Physiol 2011;589: 1515–1525. Doi:10.1113/jphysiol.2010.201855.
96. 96. Yosida M, Dezaki K, Uchida K, et al. Involvement of cAMP/EPAC/TRPM2 activation in glucose- and incretin- induced insulin secretion. Diabetes 2014; 63:3394–3403. Doi:10.2337/db13-1868.
97. 97. Shigeto M, Ramracheya R, Tarasov AI, et al. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation. J Clin Invest 2015;125: 4714– 4728. Doi:10.1172/JCI81975.
98. 98. Colsoul B, Schraenen A, Lemaire K, et al. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5-/- mice. Proc Natl Acad Sci USA 2010;107: 5208–5213. Doi:10.1073/pnas.0913107107.