Membrane Potential-Dependent Inactivation of Voltage-Gated Ion Channels in α-Cells Inhibits Glucagon Secretion From Human Islets
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OBJECTIVE: To document the properties of the voltage-gated ion channels in human pancreatic α-cells and their role in glucagon release. RESEARCH DESIGN AND METHODS: Glucagon release was measured from intact islets. [Ca2+]i was recorded in cells showing spontaneous activity at 1 mmol/l glucose. Membrane currents and potential were measured by whole-cell patch-clamping in isolated α-cells identified by immunocytochemistry. RESULTS: Glucose inhibited glucagon secretion from human islets; maximal inhibition was observed at 6 mmol/l glucose. Glucagon secretion at 1 mmol/l glucose was inhibited by insulin but not by ZnCl2. Glucose remained inhibitory in the presence of ZnCl2 and after blockade of type-2 somatostatin receptors. Human α-cells are electrically active at 1 mmol/l glucose. Inhibition of KATP-channels with tolbutamide depolarized α-cells by 10 mV and reduced the action potential amplitude. Human α-cells contain heteropodatoxin-sensitive A-type K+-channels, stromatoxin-sensitive delayed rectifying K+-channels, tetrodotoxin-sensitive Na+-currents, and low-threshold T-type, isradipine-sensitive L-type, and ω-agatoxin-sensitive P/Q-type Ca2+-channels. Glucagon secretion at 1 mmol/l glucose was inhibited by 40–70% by tetrodotoxin, heteropodatoxin-2, stromatoxin, ω-agatoxin, and isradipine. The [Ca2+]i oscillations depend principally on Ca2+-influx via L-type Ca2+-channels. Capacitance measurements revealed a rapid (<50 ms) component of exocytosis. Exocytosis was negligible at voltages below −20 mV and peaked at 0 mV. Blocking P/Q-type Ca2+-currents abolished depolarization-evoked exocytosis. CONCLUSIONS: Human α-cells are electrically excitable, and blockade of any ion channel involved in action potential depolarization or repolarization results in inhibition of glucagon secretion. We propose that voltage-dependent inactivation of these channels underlies the inhibition of glucagon secretion by tolbutamide and glucose.
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The whole-cell KATP conductance in the absence of glucose in human β-cells is <10% of that found in mouse β-cells, being around 60 pS/pF, and this difference is likely due to a lower open probability.
“However, the whole-cell KATP conductance in the absence of glucose is <10% of that found in mouse β-cells, being around 60 pS/pF (535). As there is no major difference in single-channel conductance or channel density (28), the difference is likely to be due to a lower open probability.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [535]
The Results section reports background membrane conductance in human α-cells, not KATP conductance in human β-cells. Searches for 60 pS/pF, a mouse β-cell comparison, and open probability found no passage in our copy addressing the attributed measurement. The lower-open-probability explanation is cited separately in the citing sentence. (LLM, conf=0.76)
Experimental — accuracy not yet measuredKATP channel activity in human β-cells, even at low (1 mM) glucose concentrations, is only ~10% of that in mouse β-cells.
“First, KATP channel activity in human β-cells, even at low (1 mM) glucose concentrations, is only ~10% of that in mouse β-cells (535).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [535]
The Results section on background membrane conductance reports a measurement in human α-cells at 1 mmol/l glucose, not KATP-channel activity in β-cells. Searches for human-versus-mouse β-cell KATP activity and the claimed ~10% ratio found no passage in our copy addressing that comparison. (LLM, conf=0.76)
Experimental — accuracy not yet measuredInwardly rectifying K+ channels (Kir5.1 and Kir7.1) are active in human β-cells but their contribution to resting conductance is small (10-15% of that provided by KATP channels).
“Inwardly rectifying K+ channels (Kir5.1 and Kir7.1) are also active but their contribution to the resting conductance is small (10-15% of that provided by the KATP channels) (535, 553).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [535]
The Results section on voltage-gated K+ currents describes recordings from human α-cells and mentions BK-channel currents in β-cells, but does not address Kir5.1 or Kir7.1. Searches for those channels and for the claimed 10–15% resting-conductance comparison with KATP channels found no supporting passage in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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“Moreover, SSTR-2 antagonism potently stimulated glucagon release with little effect on [Ca]pm, as is expected if somatostatin acts downstream of Ca (50, 51).”
BackgroundNeurotransmitter control of islet hormone pulsatility
Gylfe, E., & Tengholm, A. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12345 · Cited by 65 · see citing works
“Insulin was early proposed as paracrine mediator of glucoseinhibited glucagon release [70], and later studies have confirmed a direct inhibitory effect [71] and demonstrated that α-cell-specific insulin receptor knockout is associated with hyperglycaemia and hyperglucagonaemia [72].”
BackgroundRegulation of islet glucagon secretion: Beyond calcium
Hughes, J. W., Ustione, A., Lavagnino, Z., & Piston, D. W. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13381 · Cited by 75 · see citing works
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CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells
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The somatostatin receptor in human pancreatic β-cells.
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“A SSTR2 antagonist had no effect on glucagon release from human islets at 1 or 6 mM glucose (Ramracheya et al., 2010); however, it must be kept in mind that blocking SSTR2 may not be sufficient to fully antagonize the SST effects.”
BackgroundInfluentialSelf-citationFunctional identification of islet cell types by electrophysiological fingerprinting
Briant, L. J. B., Zhang, Q., Vergari, E., Kellard, J. A., Rodriguez, B., Ashcroft, F. M., & Rorsman, P. (2017) · Journal of The Royal Society Interface · doi:10.1098/rsif.2016.0999 · Cited by 59 · see citing works
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“Regardless, the role of zinc in the inhibition of glucagon secretion remains debated as other studies in human and mouse islets have shown zinc to have no effect on glucagon secretion [14,45,46].”
BackgroundParacrine Interactions Within Islets of Langerhans
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“2000b for ‘window hypothesis’), but may involved membrane potential–dependent inactivation of voltage-gated Ca channel in α-cells (Ramracheya et al. 2010).”
Pancreatic α-cells – The unsung heroes in islet function
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Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion
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Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects
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Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion
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“This corresponds to the behavior seen experimentally with the addition of tolbutamide (3,32).”
MethodTASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion
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The Role of Glucagon in the Pathophysiology and Management of Diabetes
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Metabolic Messengers: glucagon
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“Human islets Human pancreatic islets were isolated (with ethical approval and clinical consent) as previously described [14].”
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“For the acute experiments, islets were treated with sitagliptin (Stratech Scientific Ltd, Newmarket, UK), or with PYY (1-36) or PYY (3-36) (Bachem, Bubendorf, Switzerland) for 1 hour during glucose stimulation as described above.”
BackgroundMethodResultInfluentialSelf-citationDesign Principles of Pancreatic Islets: Glucose-Dependent Coordination of Hormone Pulses
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Intercellular Communication in the Islet of Langerhans in Health and Disease
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“In another controversial study, Zn 2 + was shown to stimulate glucagon secretion in human islets (304).”
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“On the other hand, depolarization in alpha cells is followed by higher action potential (AP) frequency but lower amplitude, resulting in lower calcium influx [31] and glucagon secretion.”
BackgroundZaborska, K. E., Dadi, P. K., Dickerson, M. T., Nakhe, A. Y., Thorson, A. S., Schaub, C. M., Graff, S. M., Stanley, J. E., Kondapavuluru, R. S., Denton, J. S., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101056 · Cited by 32 · see citing works
Abnormal regulation of glucagon secretion by human islet alpha cells in the absence of beta cells
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SUMO1 enhances cAMP‐dependent exocytosis and glucagon secretion from pancreatic α‐cells
Dai, X.-Q., Spigelman, A., Khan, S., Braun, M., Fox, J. E. M., & Macdonald, P. (2014) · Journal of Physiology · doi:10.1113/jphysiol.2014.274084 · Cited by 23 · see citing works
“Voltage-gated K+ (Kv) channels contribute to α-cell AP repolarization; inhibition of these blunts glucagon secretion (Ramracheya et al. 2010; Spigelman et al. 2010).”
BackgroundSelf-citationYang, L.-L., Li, Q.-M., Liu, X., & Liu, S.-G. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17091479 · Cited by 22 · see citing works
“Because glucagon secretion depends on the generation of Na+-dependent action potentials, TTX-S voltage-gated Na+ channels play a key role in regulating α cell function [64,65].”
BackgroundZhang, Q., Dou, H., & Rorsman, P. (2020) · The Journal of Physiology · doi:10.1113/jp279775 · Cited by 30 · see citing works
“…in β-cells, pharmacological inhibition of these channels in α-cells leads to suppression of glucagon secretion at 1 mM glucose (Gromada et al. 2004; Ramracheya et al. 2010; Spigelman et al. 2010), possibly by resulting in a more depolarized interspike voltage that prevents complete Na+ channel…”
BackgroundInfluentialSelf-citationAsadi, F., & Dhanvantari, S. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.726368 · Cited by 24 · see citing works
Zaborska, K. E., Jordan, K. L., Thorson, A. S., Dadi, P. K., Schaub, C. M., Nakhe, A. Y., Dickerson, M. T., Lynch, J. C., Weiss, A. J., Dobson, J. R., et al. (2022) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14747 · Cited by 21 · see citing works
Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes
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“Activation of P/Q-type CaV channels is required for GCG secretion; thus, it is probable that an interaction between α-cell TSPAN-7 and P/Q-type CaV channels regulates α-cell function (Ramracheya et al. 2010; Rorsman et al. 2012).”
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Is zinc an intra-islet regulator of glucagon secretion?
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Stamenkovic, J., Andersson, L. E., Adriaenssens, A. E., Bagge, A., Sharoyko, V. V., Gribble, F. M., Reimann, F. M., Wollheim, C. B., Mulder, H., & Spégel, P. (2015) · Biochemical Journal · doi:10.1042/bj20140697 · Cited by 17 · see citing works
Modelling of energy-driven switch for glucagon and insulin secretion
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α-cell electrophysiology and the regulation of glucagon secretion
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Self-citationChanneling dysglycemia: ion-channel variations perturbing glucose homeostasis
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A computational systems analysis of factors regulating α cell glucagon secretion
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The role of zinc in the premature brain: functions, outcomes and future research perspectives
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Per-arnt-sim (PAS) domain kinase (PASK) as a regulator of glucagon secretion
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“It is pertinent that all of these are implicated in the regulation of glucagon secretion [10, 29].”
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van Albada, M. V., Mohnike, K., Dunne, M., Banerjee, I., & Betz, S. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.921357 · Cited by 10 · see citing works
“In isolated human islets, somatostatin is released in response to increasing glucose concentrations (17).”
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Glucagonotropic and glucagonostatic effects of KATP channel closure and potassium depolarization.
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Regulation of α‐cell glucagon secretion: The role of second messengers
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“The same Cav channel may play a similar role in human α‐cell electrical activity.(42) However, it is rather counterintuitive that dihydropyridines (e.”
BackgroundSelf-citationThe relationship between glucose and the liver-alpha cell axis – A systematic review
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In vitro assessment of pancreatic hormone secretion from isolated porcine islets
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“(100-500 μM), exerts its glucagonostatic effect independently of paracrine activity via intrinsic depolarization of alpha-cell membrane and reduction of calcium entry (24, 26).”
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Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells
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“At 6 and 20 mM, glucose consumption rates of α -cells were estimated following the relative changes in glucagon secretion reported by Ramracheya et al. [50].”
BackgroundMethodInfluentialRole of cAMP in Double Switch of Glucagon Secretion
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“Cells 2021, 10, x FOR PEER REVIEW 4 of 22 the KATP channels, modulating the VDCC.”
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Tripartite cell networks for glucose homeostasis
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Modeling the Amino Acid Effect on Glucagon Secretion from Pancreatic Alpha Cells
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“On the o her hand, hyperglycemia leads to faster MP scillations, but their amplitudes are not sufficient to reach the ctivation threshold of P/Q chann ls [5,11,35,51].”
Background
- Authors
- Ramracheya, R., Ward, C., Shigeto, M., Walker, J. N., Amisten, S., Zhang, Q., Johnson, P. R., Rorsman, P., & Braun, M.
- Affiliations
- Churchill Hospital (GB)
- John Radcliffe Hospital (GB)
- Corresponding author
- Braun, Matthias
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-06-14
- Volume
- 59
- Issue
- 9
- Pages
- 2198-2208
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2927942
- OpenAlex
- W2117848154
- Cited by
- 136
- References
- 42
- Citations by year
- 2026: 9 · 2025: 2 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 10 · 2020: 13 · 2019: 12 · 2018: 8 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 11 · 2013: 4 · 2012: 11
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research
- Medical Research Council
- 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
- voltage-gated ion channels, alpha cells, glucagon secretion, human pancreatic islets, membrane potential, tolbutamide, ATP-sensitive potassium channels, A-type potassium channels, L-type calcium channels, P/Q-type calcium channels, T-type calcium channels, exocytosis, calcium oscillations, electrical excitability, insulin
- MeSH terms
- Insulin Secretion, Calcium, Chlorides, Glucagon, Glucose, Humans, Insulin, Islets of Langerhans, Membrane Potentials, Somatostatin, Tetrodotoxin, Tolbutamide, Potassium Channels, Ion Channel Gating, Zinc Compounds, Cell Culture Techniques, Glucagon-Secreting Cells
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