Voltage-dependent Na+ and Ca2+ currents in human pancreatic islet ?-cells: evidence for roles in the generation of action potentials and insulin secretion
Abstract
We describe three voltage-dependent inward currents in human pancreatic beta-cells. First, a rapidly inactivating Na+ current, blocked by tetrodotoxin (TTX) is seen upon brief depolarization to or beyond -40 mV. Second, a transient, low-voltage-activated (LVA), amiloride-blockable Ca2+ current is seen upon depolarization to or beyond -55 mV; it inactivates within less than 1s of sustained depolarization to -40 mV. Third, a more sustained, high-voltage-activated (HVA) Ca2+ current, which shows variable sensitivity to dihydropyridines is seen upon depolarization to or beyond -40 mV, and thereafter slowly inactivates over a time course of many seconds. Our pharmacological evidence suggests that all three currents contribute to action potential initiation and upstroke when the background membrane potential (Vm) is equal or negative to -45 to -40 mV, a situation often induced by glucose concentrations (5-6 mM) in the range of those seen post-prandially. Consistent with this, TTX drastically reduces both transient and sustained insulin secretion in the presence of 5-6 mM glucose, but has little effect in 10 mM glucose, at which concentration cells rapidly depolarize to approximately -35 mV, a Vm sufficient to rapidly inactivate Na+ and LVA Ca2+ currents.
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TTX reduces insulin secretion in human β-cells, with its effect particularly strong at 6 mM glucose and weaker at 10-20 mM glucose.
“Furthermore, TTX reduces insulin secretion: its effect is particularly strong at glucose concentrations just above the threshold for GIIS (6 mM) but is weaker at higher (10-20 mM) concentrations (52, 90) (see Figure 13C-D).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [52]
Human β-cells (unlike mouse β-cells) are equipped with T-type Ca2+-channels that activate at membrane potentials as negative as -60 mV.
“Second, human β-cells (unlike mouse β-cells) are equipped with T-type Ca2+-channels that activate at membrane potentials as negative as -60 mV (52, 90).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [52]
Na+ channels play a particularly important role at glucose concentrations just above the threshold for triggering electrical activity in human β-cells.
“Na+ channels play a particularly important role at glucose concentrations just above the threshold for triggering electrical activity (52, 90).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [52]
The membrane potential during interspike intervals in human β-cells may be as negative as -60 mV at 6 mM glucose, but is between -50 and -40 mV at 10 mM glucose or above.
“This may be seen from the fact that the membrane potential during the interspike intervals may be as negative as -60 mV at 6 mM glucose, (89), but is between -50 and -40 mV at 10 mM glucose or above (52) (Figure 6 and schematic in Figure 13C-D).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [52]
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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
Rorsman, P., & Braun, M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183754 · Cited by 599 · see citing works
Voltage‐gated and resting membrane currents recorded from B‐cells in intact mouse pancreatic islets
Göpel, S., Kanno, T., Barg, S., Galvanovskis, J., & Rorsman, P. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.00717.x · Cited by 226 · see citing works
- Authors
- Barnett, D. W., Pressel, D. M., & Misler, S.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Barnett, David W.
- Venue
- Pfl�gers Archiv European Journal of Physiology
- Published
- 1995-12
- Volume
- 431
- Issue
- 2
- Pages
- 272-282
- ISSN
- 0031-6768 (ISSN-L)
- 1432-2013
- OpenAlex
- W1969252369
- Cited by
- 100
- References
- 0
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 4 · 2019: 2 · 2018: 10 · 2017: 6 · 2016: 2 · 2015: 5 · 2014: 13 · 2013: 6 · 2012: 1
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Pflügers Archiv - European Journal of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk037380-12)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37380)
- 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, voltage-dependent sodium current, low-voltage-activated calcium current, high-voltage-activated calcium current, action potential generation, insulin secretion, tetrodotoxin, amiloride, dihydropyridines, membrane potential, glucose concentration, postprandial blood glucose
- MeSH terms
- Action Potentials, Amiloride, Calcium Channel Blockers, Diuretics, Electrophysiology, Humans, Insulin, Islets of Langerhans, Membrane Potentials, Nifedipine, Tetrodotoxin, Calcium Channels, Sodium Channels, Ion Channel Gating, Patch-Clamp Techniques, In Vitro Techniques
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