Electrophysiology of Islet Cells
Abstract
Stimulus-Secretion Coupling (SSC) of pancreatic islet cells comprises electrical activity. Changes of the membrane potential (V(m)) are regulated by metabolism-dependent alterations in ion channel activity. This coupling is best explored in beta-cells. The effect of glucose is directly linked to mitochondrial metabolism as the ATP/ADP ratio determines the open probability of ATP-sensitive K(+) channels (K(ATP) channels). Nucleotide sensitivity and concentration in the direct vicinity of the channels are controlled by several factors including phospholipids, fatty acids, and kinases, e.g., creatine and adenylate kinase. Closure of K(ATP) channels leads to depolarization of beta-cells via a yet unknown depolarizing current. Ca(2+) influx during action potentials (APs) results in an increase of the cytosolic Ca(2+) concentration ([Ca(2+)](c)) that triggers exocytosis. APs are elicited by the opening of voltage-dependent Na(+) and/or Ca(2+) channels and repolarized by voltage- and/or Ca(2+)-dependent K(+) channels. At a constant stimulatory glucose concentration APs are clustered in bursts that are interrupted by hyperpolarized interburst phases. Bursting electrical activity induces parallel fluctuations in [Ca(2+)](c) and insulin secretion. Bursts are terminated by I(Kslow) consisting of currents through Ca(2+)-dependent K(+) channels and K(ATP) channels. This review focuses on structure, characteristics, physiological function, and regulation of ion channels in beta-cells. Info…
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At 10 mM glucose, the active and silent phases last 5-10 s and 10-20 s, respectively, with 2-4 bursts/min.
“At 10 mM glucose, the active and silent phases last 5-10 s and 10-20 s, respectively and there are 2-4 bursts/min (154, 273, 570).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [154]
Somatostatin and adrenaline transiently repolarise the β-cell and inhibit action potential firing and insulin secretion.
“A number of hormones and neurotransmitters (e.g. somatostatin and adrenaline) transiently repolarise the β-cell and inhibit action potential firing and insulin secretion (154, 543).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [154]
Increasing glucose concentrations produce a progressive increase in burst duration at the expense of repolarized intervals until firing becomes continuous, usually above ~20 mM glucose.
“Increasing glucose concentrations produce a progressive increase in burst duration at the expense of the repolarized intervals until firing finally becomes continuous, usually above ~20 mM glucose (154, 273).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [154]
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“The ATP hydrolysis occurs in NBD1, which is a high-affinity site for ATP or MgATP, whereas NBD2 has low-affinity to MgATP orMgADP and intrinsic ATPase activity (Drews et al., 2010; Yang et al., 2014a).”
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“The electrical activities and the [Ca2+]i oscillations are generated by concerted participation of a unique repertoire of ion channels present in the β-cells [4].”
BackgroundMathematical models of pancreatic islet size distributions
Jo, J., Hara, M., Ahlgren, U., Sorenson, R., & Periwal, V. (2012) · Islets · doi:10.4161/isl.18660 · Cited by 33 · see citing works
Kong, X.-C., Tu, Y.-F., Li, B.-F., Zhang, L.-M., Feng, L., Wang, L.-X., Zhang, L., Zhou, H.-R., Hua, X., & Ma, X.-S. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.08.009 · Cited by 32 · see citing works
“The transient receptor potential (TRP) channels have been hypothesized to be responsible for this inward cation current [9,10].”
BackgroundLupanine Improves Glucose Homeostasis by Influencing KATP Channels and Insulin Gene Expression
Wiedemann, M., Gurrola-Díaz, C., Vargas-Guerrero, B., Wink, M., García-López, P., & Düfer, M. (2015) · Molecules · doi:10.3390/molecules201019085 · Cited by 32
“, by mechanisms elevating intracellular cAMP concentration [12].”
BackgroundSelf-citationLiu, L., Wang, F., Lu, H.-Y., Ren, X.-M., & Zou, J.-H. (2014) · Islets · doi:10.4161/19382014.2014.962386 · Cited by 31 · see citing works
Transient Receptor Potential (TRP) Cation Channels in Diabetes
Colsoul, B., Nilius, B., & Vennekens, R. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026611313030004 · Cited by 24 · see citing works
Involvement of aquaglyceroporins in energy metabolism in health and disease.
Calamita, G., & Delporte, C. (2021) · Biochimie · doi:10.1016/j.biochi.2021.03.001 · Cited by 30 · see citing works
Mourad, N., Nenquin, M., & Henquin, J. (2012) · Endocrinology · doi:10.1210/en.2012-1450 · Cited by 30 · see citing works
Kv1.3: a potential pharmacological target for diabetes
Choi, B.-H., & Hahn, S. (2010) · Acta Pharmacologica Sinica · doi:10.1038/aps.2010.133 · Cited by 30 · see citing works
High-resolution analysis of the cytosolic Ca2+ events in β cell collectives in situ
Postić, S., Sarikas, S., Pfabe, J., Pohorec, V., Bombek, L. K., Sluga, N., Klemen, M. S., Dolenšek, J., Korošak, D., Stožer, A., et al. (2021) · bioRxiv · doi:10.1101/2021.04.14.439796 · Cited by 29
Sakuma, K., Yabuki, C., Maruyama, M., Abiru, A., Komatsu, H., Negoro, N., Tsujihata, Y., Takeuchi, K., Habata, Y., & Mori, M. (2016) · Pharmacology Research & Perspectives · doi:10.1002/prp2.237 · Cited by 29 · see citing works
“Membrane depolarization of b-cells is necessary for the insulinotropic effect of fasiglifam Membrane depolarization is a fundamental event in the integration of excitatory signals during glucose-induced insulin secretion (MacDonald and Rorsman 2006; Drews et al. 2010).”
BackgroundArous, C., Ferreira, P., Dermitzakis, E., & Halban, P. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.611111 · Cited by 28
“This rise in cytosolic Ca(2) stems from glucose metabolism, closure of ATPsensitive potassium channels, depolarization, opening of voltage-gated calcium channels, and calcium influx (41).”
BackgroundPfeiffer, T., Kraushaar, U., Düfer, M., Schönecker, S., Haspel, D., Günther, E., Drews, G., & Krippeit-Drews, P. (2011) · Pflügers Archiv: European Journal of Physiology · doi:10.1007/s00424-011-1029-z · Cited by 27 · see citing works
“Pancreatic beta-cells are unique as they exhibit oscillatory electrical activity known as slow waves in response to glucose [7].”
BackgroundMethodInfluentialSelf-citationChang, H., Chen, S.-L., Shen, M., Kung, M.-L., Chuang, L.-M., & Chen, Y.-W. (2017) · Scientific Reports · doi:10.1038/s41598-017-03747-0 · Cited by 26 · see citing works
Teyani, R. L., & Moniri, N. H. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16225 · Cited by 25 · see citing works
“…glucose stimulus used to drive GSIS in these studies is variable in the non-basal state and ranges from 12 to 25 mM, which could produce differential levels of glycolysis and subsequent ATP:ADP ratios that drive depolarization-dependent insulin secretion (Drews et al., 2010; Morsi et al., 2020).”
BackgroundMetabolic amplification of insulin secretion by glucose is independent of β-cell microtubules.
Mourad, N., Nenquin, M., & Henquin, J. (2011) · American Journal of Physiology - Cell Physiology · doi:10.1152/ajpcell.00329.2010 · Cited by 24 · see citing works
Henquin, J., Mourad, N., & Nenquin, M. (2012) · FEBS Letters · doi:10.1016/j.febslet.2011.11.030 · Cited by 23 · see citing works
Alshahrani, S., & Difulvio, M. (2012) · Journal of Endocrinology · doi:10.1530/joe-12-0244 · Cited by 22 · see citing works
“This depolarisation gates voltage-dependent Ca2C channels promoting Ca2C influx, the trigger for exocytosis of insulin stored in granules (Drews et al. 2010).”
BackgroundMears, D., Zimliki, C., Atwater, I., Rojas, E., Glassman, M., Leighton, X., Pollard, H., & Srivastava, M. (2012) · Cellular Physiology and Biochemistry · doi:10.1159/000186926 · Cited by 22
Role of TRP Channels in Metabolism-Related Diseases
Wu, F., Bu, S., & Wang, H.-M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020692 · Cited by 21 · see citing works
“When the plasma membrane depolarizes to − 50 mV, the voltage-gated calcium channel opens, causing Ca 2+ inflow and an increase in cytoplasmic calcium ion concentration, and the increase in intracellular Ca 2+ concentration triggers the exocytosis of insulin-containing vesicles in β cells [85,86].”
BackgroundEsculentin-2CHa(1-30) and its analogues: stability and mechanisms of insulinotropic action.
Vasu, S., McGahon, M., Moffett, R., Curtis, T., Conlon, J., Abdel-Wahab, Y., & Flatt, P. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0453 · Cited by 21 · see citing works
“…detect the changes in blood glucose levels, and subsequent metabolism leads to increase in ATP levels that induces closure of plasma membrane K ATP channels and depolarisation resulting in the opening of voltage-gated Ca 2+ channels (VDCC) (McClenaghan 2007, Drews et al. 2010, Fu et al. 2013).”
BackgroundGarcía-Delgado, N., Velasco, M., Sánchez-Soto, C., Díaz-García, C. M., & Hiriart, M. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00040 · Cited by 19
Jensen, M., Haldeman, J. M., Zhang, H.-T., Lu, D.-H., Huising, M., Vale, W., Hohmeier, H., Rosenberg, P. A., & Newgard, C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.491654 · Cited by 19 · see citing works
Calcium Channels As Therapeutic Targets
Belardetti, F., & Spacey, S. (2012) · Wiley Interdisciplinary Reviews Membrane Transport and Signalling · doi:10.1002/wmts.38 · Cited by 19 · see citing works
Henquin, J. (2017) · Biochimie · doi:10.1016/j.biochi.2017.07.002 · Cited by 18 · see citing works
“In both mouse and human β-cells, it is generated by closure of KATP channels in 89 the plasma membrane, which permits depolarization to the threshold potential at which voltage90 gated calcium channels open and allow Ca 2+ influx into the cell [9-14].”
BackgroundAtrial Natriuretic Peptide Affects Stimulus-Secretion Coupling of Pancreatic β-Cells
Undank, S., Kaiser, J. K., Sikimić, J., Düfer, M., Krippeit-Drews, P., & Drews, G. (2017) · Diabetes · doi:10.2337/db17-0392 · Cited by 18 · see citing works
“RPMI1640 medium was from PromoCell (Heidelberg, Germany), penicillin/streptomycin from Gibco BRL (Karlsruhe, Germany), atrial natriuretic factor (1-28) (mouse, rabbit, rat) trifluoroacetate salt from Bachem (Weil am Rhein, Germany), Rp-8-Br-PET-cGMPS from Biolog (Bremen, Germany), and PKI 14-22 amide, myristoylated (m…”
BackgroundMethodSelf-citationPohorec, V., Bombek, L. K., Klemen, M. S., Dolenšek, J., & Stožer, A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.867663 · Cited by 17 · see citing works
Ca-induced Ca Release from Internal Stores in INS-1 Rat Insulinoma Cells.
Choi, K., Dong, S.-C., Kim, J., Kim, B., Lee, K. M., Kim, S.-H., Kim, D. K., Kim, S. H., & Park, H. (2011) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2011.15.1.53 · Cited by 16
“The depolarization of plasma membranes for activation of voltage-gated Ca channels (CaV) is one of the most critical events leading to a rise in [Ca]i and insulin secretion in β-cell [1-3,27,28].”
BackgroundWilhelmi, I., Grunwald, S., Gimber, N., Popp, O., Dittmar, G., Arumughan, A., Wanker, E., Laeger, T., Schmoranzer, J., Daumke, O., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101151 · Cited by 15 · see citing works
“ATP-sensitive potassium channels in the plasma membrane are closed due to a rising ATP:ADP ratio, leading to membrane depolarization, followed by opening of voltage-dependent Ca 2 þ channels [5 e 7].”
Possible New Strategies for the Treatment of Congenital Hyperinsulinism
Sikimić, J., Hoffmeister, T., Gresch, A., Kaiser, J. K., Barthlen, W., Wolke, C., Wieland, I., Lendeckel, U., Krippeit-Drews, P., Düfer, M., et al. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.545638 · Cited by 15 · see citing works
“This points to alterations in mitochondrial metabolism, which can cause changes in KATP channel activity independent of any direct interaction with the channel proteins (72).”
BackgroundSelf-citationExpression and function of ATP-dependent potassium channels in zebrafish islet β-cells
Emfinger, C. H., Welscher, A., Yan, Z., Wang, Y., Conway, H., Moss, J. B., Moss, L. G., Remedi, M. S., & Nichols, C. G. (2017) · Royal Society Open Science · doi:10.1098/rsos.160808 · Cited by 14 · see citing works
“In the pancreatic β-cell, ATP-sensitive potassium (KATP) channels link glucose metabolism and insulin secretion and are essential to the normal regulation of plasma glucose and other nutrients [1,2].”
BackgroundChanneling dysglycemia: ion-channel variations perturbing glucose homeostasis
Denton, J. S., & Jacobson, D. A. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.09.004 · Cited by 14 · see citing works
“Depolarization of the islet membrane activates many ion channels including VDCCs, voltage-gated sodium (NaV) channels, and potassium channels, whereas, hyperpolarization inactivates these channels [1, 3, 8, 23].”
BackgroundPancreatic beta-cells: Role of glycerol and aquaglyceroporin 7.
Virreira, M., Perret, J., & Delporte, C. (2011) · International Journal of Biochemistry and Cell Biology · doi:10.1016/j.biocel.2010.10.018 · Cited by 14 · see citing works
“…to hypotonic extracellular solutions induce cell swelling, activating volume-regulated anion channel (VRAC) and cell membrane depolarization, leading to activation of voltage-sensitive calcium channels, allowing calcium entry, and thereby insulin exocytosis (Best et al., 1996; Drews et al., 2010).”
BackgroundRegulatory effects of protein S-acylation on insulin secretion and insulin action
Chamberlain, L., Shipston, M., & Gould, G. (2021) · Open Biology · doi:10.1098/rsob.210017 · Cited by 13 · see citing works
Cieślak, M., & Roszek, K. (2014) · Acta Biochimica Polonica · doi:10.18388/abp.2014_1827 · Cited by 13 · see citing works
“On the contrary, stimulation of the sympathetic nerve endings inhibits insulin secretion by affecting the α2A adrenoceptor acting through the ATP-dependent K+-channel (Drews et al., 2010; Burnstock, 2013).”
BackgroundA computational systems analysis of factors regulating α cell glucagon secretion
Fridlyand, L. E., & Philipson, L. H. (2012) · Islets · doi:10.4161/isl.22193 · Cited by 12 · see citing works
Evidence against a Ca2+-induced potentiation of dehydrogenase activity in pancreatic beta-cells
Drews, G., Bauer, C., Edalat, A., Düfer, M., & Krippeit-Drews, P. (2015) · Pflügers Archiv: European Journal of Physiology · doi:10.1007/s00424-015-1707-3 · Cited by 12 · see citing works
Self-citationLanglhofer, G., Kögel, A., & Schaefer, M. (2021) · Cell Calcium · doi:10.1016/j.ceca.2021.102469 · Cited by 10 · see citing works
Leech, C. A., Kopp, R., Nelson, H. A., Nandi, J., & Roe, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.767681 · Cited by 11 · see citing works
“2 L-type Ca(2) channels (28 –30) that is important for triggering insulin secretion (31, 32).”
Gil-Rivera, M., Medina-Gali, R., Martinez-Pinna, J., & Soriano, S. (2021) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2021.02.006 · Cited by 11 · see citing works
Gresch, A., & Düfer, M. (2020) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.120.265835 · Cited by 10 · see citing works
Self-citationBrouwer, S., Hoffmeister, T., Gresch, A., Schönhoff, L., & Düfer, M. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700902 · Cited by 10 · see citing works
Self-citationYuan, Y., Wang, H., Jiang, Z.-J., Liu, C., Li, Q., Zhou, S., & Yang, J.-K. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01923-z · Cited by 9 · see citing works
Guzmán, T. J., Klöpper, N., Gurrola-Díaz, C. M., & Düfer, M. (2024) · Biogerontology (Dordrecht) · doi:10.1007/s10522-024-10107-9 · Cited by 9 · see citing works
“A proper calcium handling is highly relevant for electrically excitable cells, since the electrical activity is closely coupled to changes in the cytosolic calcium concentrations (Drews et al. 2010).”
BackgroundSelf-citationAdeyemi, W., & Olayaki, L. (2019) · Synergy · doi:10.1016/j.synres.2018.100045 · Cited by 9 · see citing works
Zhao, Y.-F., Wang, L., Zha, D., Qiao, L., Lu, L.-J., Yu, J., Qu, P., Sun, Q., Qiu, J.-H., & Chen, C. (2013) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0019 · Cited by 9 · see citing works
“…to generate ATP from ADP, and the increased ATP:ADP ratio closes KATP channels and leads to membrane depolarization and a concomitant rise in the levels of intracellular Ca2C concentration ([Ca2C]i) and insulin secretion (Ashcroft et al. 1994, Rorsman 1997, Drews et al. 2010, Rorsman et al. 2011).”
BackgroundTriton X‐100 inhibits L‐type voltage‐operated calcium channels
Narang, D., Kerr, P., Baserman, J. N., Tam, R., Yang, W., Searle, G. J., Fox, J. E. M., Paulsen, I. M., Kozuska, J. L., Macdonald, P., et al. (2012) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2012-0257 · Cited by 9 · see citing works
Chloride channels and transporters in β-cell physiology
Difulvio, M., Brown, P., & Aguilar-Bryan, L. (2014) · doi:10.1007/978-94-007-6686-0_34 · Cited by 9
“Naturally, electrogenic Cl efflux modulates membrane depolarization in response to glucose and therefore stimulates insulin secretion (Best et al. 2010; Drews et al. 2010).”
BackgroundCalamita, G., & Delporte, C. (2023) · Cells · doi:10.3390/cells12172170 · Cited by 8 · see citing works
“The latter allows calcium entry which triggers insulin secretion [288,289].”
BackgroundComparative analysis of reconstructed architectures from mice and human islets
Félix-Martínez, G. J., & Godínez-Fernández, J. R. (2021) · Islets · doi:10.1080/19382014.2021.1987827 · Cited by 8 · see citing works
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Pajaziti, B., Yosy, K., Steinberg, O. V., & Düfer, M. (2022) · Pflügers Archiv: European Journal of Physiology · doi:10.1007/s00424-022-02772-x · Cited by 6 · see citing works
Self-citation
- Authors
- Drews, G., Krippeit-Drews, P., & Düfer, M.
- Affiliations
- University of Tübingen (DE)
- Corresponding author
- Drews, Gisela
- Venue
- Advances in Experimental Medicine and Biology
- Publisher
- Springer Netherlands
- Published
- 2010
- Volume
- 654
- Pages
- 115-163
- ISSN
- 0065-2598 (ISSN-L)
- OpenAlex
- W1886288445
- Cited by
- 152
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 9 · 2022: 8 · 2021: 14 · 2020: 7 · 2019: 4 · 2018: 10 · 2017: 11 · 2016: 4 · 2015: 10 · 2014: 15 · 2013: 16 · 2012: 16
- FWCI
- 135.74
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Advances in experimental medicine and biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- pancreatic beta cells, stimulus-secretion coupling, ATP-sensitive potassium channels, beta-cell electrical activity, glucose-stimulated insulin secretion, L-type calcium channels, oxidative stress, alpha cells, delta cells, ion channels, membrane potential, exocytosis, voltage-gated sodium channels
- MeSH terms
- Adenosine Triphosphate, Animals, Calcium, Cell Membrane, Electrophysiology, Glucose, Humans, Ion Channels, Islets of Langerhans, Membrane Potentials, Oscillometry, Potassium Channels, Mice, Knockout, Oxidative Stress, Mice
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