Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses: Kv and K Ca regulation of islet electrical activity
Open accessAbstract
Glucose-induced β-cell action potential (AP) repolarization is regulated by potassium efflux through voltage gated (Kv) and calcium activated (K(Ca)) potassium channels. Thus, ablation of the primary Kv channel of the β-cell, Kv2.1, causes increased AP duration. However, Kv2.1(-/-) islet electrical activity still remains sensitive to the potassium channel inhibitor tetraethylammonium. Therefore, we utilized Kv2.1(-/-) islets to characterize Kv and K(Ca) channels and their respective roles in modulating the β-cell AP. The remaining Kv current present in Kv2.1(-/-) β-cells is inhibited with 5 μM CP 339818. Inhibition of the remaining Kv current in Kv2.1(-/-) mouse β-cells increased AP firing frequency by 39.6% but did not significantly enhance glucose stimulated insulin secretion (GSIS). The modest regulation of islet AP frequency by CP 339818 implicates other K(+) channels, possibly K(Ca) channels, in regulating AP repolarization. Blockade of the K(Ca) channel BK with slotoxin increased β-cell AP amplitude by 28.2%, whereas activation of BK channels with isopimaric acid decreased β-cell AP amplitude by 30.6%. Interestingly, the K(Ca) channel SK significantly contributes to Kv2.1(-/-) mouse islet AP repolarization. Inhibition of SK channels decreased AP firing frequency by 66% and increased AP duration by 67% only when Kv2.1 is ablated or inhibited and enhanced GSIS by 2.7-fold. Human islets also express SK3 channels and their β-cell AP frequency is significantly accelerated by…
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BK channels are blocked by peptide toxins such as charybdotoxin, iberiotoxin and slotoxin, and by the alkaloid paxilline.
“They are also blocked by peptide toxins such as charybodotoxin, iberiotoxin and slotoxin (293, 311)), and by the alkaloid paxilline (293).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
Pharmacological activation of SK channels using riluzole in mouse β-cells exposed to tolbutamide leads to a prompt membrane repolarization that is reversed by apamin.
“Conversely, pharmacological activation of SK channels using riluzole in mouse β-cells exposed to tolbutamide leads to a prompt membrane repolarization that is reversed by apamin (311).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
Blocking SK channels with apamin, or the non-selective antagonist NS8593, results in membrane depolarization and action potential firing in human β-cells and stimulates insulin secretion.
“Blocking SK channels with apamin, or the non-selective antagonist NS8593, results in membrane depolarization and action potential firing in human β-cells (311) and stimulates insulin secretion (568).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
SK channels are expressed in mouse β-cells, are functionally active, and contribute to action potential and burst repolarization.
“Collectively, this pharmacological profile suggests that SK channels not only are expressed in mouse β-cells but also are functionally active and contribute to action potential and burst repolarization.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
When apamin is applied to β-cells lacking functional Kv2.1 channels, a dramatic increase in action potential duration is observed.
“However, when apamin is applied to β-cells lacking functional Kv2.1 channels (due to genetic ablation or pharmacological inhibition), a dramatic increase in action potential duration is observed (311).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
Pancreatic β-cells from mice lacking Kv2.1 channels show complex action potentials with signs of 're-entry'.
“Pancreatic β-cells from mice lacking Kv2.1 channels show complex action potentials with signs of ‘re-entry’: i.e. a new action potential is triggered during the downstroke of the previous one (311).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
The SK1-3 antagonist NS8593 produced a 10-mV depolarization, increased action potential firing and strongly potentiated insulin secretion evoked by 10 mM glucose in human islets.
“Support for the role of SK channels comes from the fact that the SK1-3 antagonist NS8593 produced a 10-mV depolarization, increased action potential firing and strongly potentiated insulin secretion evoked by 10 mM glucose in human islets (311).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
Apamin (a blocker of SK1, SK2 and SK3 channels) stimulates action potential firing in human β-cells and reduces action potential height.
“Apamin (a blocker of SK1, SK2 and SK3 channels) stimulates action potential firing in human β-cells and reduces action potential height (311).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [311]
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“1−/− islets may also help to understand this aspect of human islet function (Braun et al. 2008).”
BackgroundInfluentialMunc18-1 Promotes Large Dense-Core Vesicle Docking
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“A brief light pulse at 360 nm was applied to the cell through the monochrometer at full intensity to release a small quantity of calcium in the cytoplasm as described (Voets et al. 2001).”
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Regulation of Insulin Secretion in Human Pancreatic Islets
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Glucocorticoids Reprogram β-Cell Signaling to Preserve Insulin Secretion
Fine, N. H. F., Doig, C. L., Elhassan, Y. S., Vierra, N. C., Marchetti, P., Bugliani, M., Nano, R., Piemonti, L., Rutter, G. A., Jacobson, D. A., et al. (2018) · Diabetes · doi:10.2337/db16-1356 · Cited by 61 · see citing works
Self-citation
- Authors
- Jacobson, D. A., Mendez, F., Thompson, M., Torres, J., Cochet, O., & Philipson, L. H.
- Affiliations
- Vanderbilt University (US)
- University of Chicago (US)
- Corresponding author
- Jacobson, David A.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2010-09-15
- Volume
- 588
- Issue
- 18
- Pages
- 3525-3537
- ISSN
- 0022-3751 (ISSN-L)
- PMC
- PMC2988516
- OpenAlex
- W1746749941
- Cited by
- 73
- References
- 4
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 3 · 2015: 8 · 2014: 11 · 2013: 4 · 2012: 6
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Chicago
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048494, DK081666-02, DK020595, DK-48494, K01DK081666, P60DK020595, P30DK020595)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- pancreatic beta cells, potassium channels, Kv2.1, calcium-activated potassium channels, small conductance calcium-activated potassium channels, BK channels, action potential repolarization, glucose-stimulated insulin secretion, isopimaric acid, apamin
- MeSH terms
- Aminoquinolines, Animals, Calcium, Evoked Potentials, Glucose, Humans, Hypoglycemic Agents, Imines, Mice, Inbred C57BL, Quinolines, Tolbutamide, Mice, Knockout, Potassium Channels, Voltage-Gated, Potassium Channels, Calcium-Activated, Insulin-Secreting Cells, Mice, Electrophysiological Phenomena
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