Regulation of glucagon release in mouse α‐cells by KATP channels and inactivation of TTX‐sensitive Na+ channels
Open accessAbstract
The perforated patch whole-cell configuration of the patch-clamp technique was applied to superficial glucagon-secreting alpha-cells in intact mouse pancreatic islets. alpha-cells were distinguished from the beta- and delta-cells by the presence of a large TTX-blockable Na+ current, a TEA-resistant transient K+ current sensitive to 4-AP (A-current) and the presence of two kinetically separable Ca2+ current components corresponding to low- (T-type) and high-threshold (L-type) Ca2+ channels. The T-type Ca2+, Na+ and A-currents were subject to steady-state voltage-dependent inactivation, which was half-maximal at -45, -47 and -68 mV, respectively. Pancreatic alpha-cells were equipped with tolbutamide-sensitive, ATP-regulated K+ (KATP) channels. Addition of tolbutamide (0.1 mM) evoked a brief period of electrical activity followed by a depolarisation to a plateau of -30 mV with no regenerative electrical activity. Glucagon secretion in the absence of glucose was strongly inhibited by TTX, nifedipine and tolbutamide. When diazoxide was added in the presence of 10 mM glucose, concentrations up to 2 microM stimulated glucagon secretion to the same extent as removal of glucose. We conclude that electrical activity and secretion in the alpha-cells is dependent on the generation of Na+-dependent action potentials. Glucagon secretion depends on low activity of KATP channels to keep the membrane potential sufficiently negative to prevent voltage-dependent inactivation of voltage-gated membrane currents. Glucose may inhibit glucagon release by depolarising the alpha-cell with resultant inactivation of the ion channels participating in action potential generation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In isolated mouse alpha cells with low KATP channel density, the inhibitory effect of glucose dominated, although closure of the KATP channels themselves was modestly stimulatory.
“In isolated mouse alpha cells with low K ATP channel density [13,44] the inhibitory effect of glucose dominated, although closure of the K ATP channels themselves was modestly stimulatory.”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [13]
The small store-operated current is sufficient to trigger voltage-dependent Ca2+ influx because of the high input resistance and the fact that action potentials start at voltages as negative as -60 mV.
“The small store-operated current is sufficient to trigger voltagedependent Ca 2+ influx because of the high input resistance [12] and the fact that the action potentials start at voltages as negative as -60 mV [13,39,43].”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [13]
Rat alpha cells have much higher KATP channel density than mouse alpha cells.
“Similar evidence has been obtained with rat alpha cells, which have much higher K ATP channel density [43] than mouse alpha cells [13,44].”
From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [13]
Mouse alpha-cells show little KATP channel expression, corresponding to 2% of that in mouse beta-cells.
“mouse ␣-cells show little K ATP channel expression (25,26), corresponding to 2% of that in mouse -cells (27).”
From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [26]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Ion Channels/Excitable Membranes
(2011) · Springer eBooks · doi:10.1007/springerreference_33998 · Cited by 4,066 · see citing works
Ion Channels/Excitable Membranes
Terlau, H., & Kirchhoff, F. (2006) · Springer eBooks · doi:10.1007/3-540-29623-9_5640 · Cited by 1,805 · see citing works
Electrophysiology of the pancreatic β-cell
Ashcroft, F. M., & Rorsman, P. (1989) · Progress in Biophysics and Molecular Biology · doi:10.1016/0079-6107(89)90013-8 · Cited by 1,127 · see citing works
Self-citationClasses of Calcium Channels in Vertebrate Cells
Bean, B. P. (1989) · Annual Review of Physiology · doi:10.1146/annurev.ph.51.030189.002055 · Cited by 1,074 · see citing works
Molecular characterization of a neuronal low-voltage-activated T-type calcium channel
Perez‐Reyes, E., Cribbs, L. L., Daud, A. N., Lacerda, A. E., Barclay, J., Williamson, M. P., Fox, M., Rees, M., & Lee, J. (1998) · Nature · doi:10.1038/36110 · Cited by 736 · 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
Self-citationGromada, J., Bokvist, K., Ding, W.-G., Barg, S., Buschard, K., Renström, E., & Rorsman, P. (1997) · The Journal of General Physiology · doi:10.1085/jgp.110.3.217 · Cited by 196 · see citing works
Self-citationNadal, Á., Quesada, I., & Soria, B. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.0085z.x · Cited by 196 · see citing works
Heimberg, H., De Vos, A., Pipeleers, D., Thorens, B., & Schuit, F. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.15.8971 · Cited by 188 · see citing works
Detimary, P., Dejonghe, S., Ling, Z., Pipeleers, D., Schuit, F., & Henquin, J.-C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.51.33905 · Cited by 159 · cited 2× · see citing works
“This contrasts to the situation in â_cells where the ATPÏADP ratio increases from 2·5 at 1 mÒ glucose to > 12 at glucose concentrations ü 10 mÒ (Detimary et al. 1998).”
BackgroundPatch‐clamp characterisation of somatostatin‐secreting δ‐cells in intact mouse pancreatic islets
Göpel, S., Kanno, T., Barg, S., & Rorsman, P. (2000) · The Journal of Physiology · doi:10.1111/j.1469-7793.2000.00497.x · Cited by 143 · see citing works
Self-citationGöpel, S. O., Kanno, T., Barg, S., Eliasson, L., Galvanovskis, J., Renström, E., & Rorsman, P. (1999) · The Journal of General Physiology · doi:10.1085/jgp.114.6.759 · Cited by 137 · see citing works
Self-citationCharacterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells
Bokvist, K., Olsen, H. L., Høy, M., Gotfredsen, C. F., Holmes, W. F., Buschard, K., Rorsman, P., & Gromada, J. (1999) · Pflügers Archiv · doi:10.1007/s004249900076 · Cited by 132 · see citing works
Self-citationQuesada, I., Nadal, A., & Soria, B. (1999) · Diabetes · doi:10.2337/diabetes.48.12.2390 · Cited by 99 · cited 2× · see citing works
“The low KATP channel density is in accordance with the reported weak binding of fluorescently labelled glibenclamide to dispersed á_cells maintained in tissue culture (Quesada et al. 1999).”
BackgroundResultRorsman, P., & Hellman, B. (1988) · The Journal of general physiology · doi:10.1085/jgp.91.2.223 · Cited by 97 · see citing works
Self-citationCampbell, D. L., Qu, Y., Rasmusson, R. L., et al. (1993) · The Journal of General Physiology · doi:10.1085/jgp.101.4.603 · Cited by 86 · see citing works
Na+ currents in cultured mouse pancreatic B-cells
Plant, T. D. (1988) · Pfl�gers Archiv European Journal of Physiology · doi:10.1007/bf00587723 · Cited by 85 · see citing works
Yoshimoto, Y., Fukuyama, Y., Horio, Y., Inanobe, A., Gotoh, M., & Kurachi, Y. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00076-9 · Cited by 80 · see citing works
Mêda, P., Santos, R. M., & Atwater, I. J. (1986) · Diabetes · doi:10.2337/diab.35.2.232 · Cited by 52 · see citing works
Suppression of Ca2+ oscillations in glucagon-producing α2-cells by insulin/glucose and amino acids
Berts, A., Ball, A., Gylfe, E., & Hellman, B. (1996) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/0167-4889(95)00173-5 · Cited by 50 · see citing works
Rorsman, P. (1988) · The Journal of General Physiology · doi:10.1085/jgp.91.2.243 · Cited by 41 · see citing works
Self-citationSchwanstecher, C., Dickel, C., Ebers, I., Lins, S., Zünkler, B. J., & Panten, U. (1992) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1992.tb14467.x · Cited by 35 · see citing works
Demonstration of A-currents in pancreatic islet cells
Smith, P. A., Bokvist, K. B., & Rorsman, P. (1989) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/bf00584497 · Cited by 23 · see citing works
Self-citationAlloxan reversibly impairs glucagon release and glucose oxidation by pancreatic A2-cells
Östenson, C. (1980) · Biochemical Journal · doi:10.1042/bj1880201 · Cited by 16 · see citing works
Conley, E. C. (1999) · Elsevier eBooks · doi:10.1016/b978-012184453-0/50014-7 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Conley EC. VLG Kv4-Shal. In: Conley EC, Brammar WJ, editors. The Ion Channel Facts Book: Voltage-gated channels. Vol. 4. San Diego: Academic Press; 1999. pp. 617–646. [Google Scholar]
Cited by
Sorted by citations
Stern, J. H., Rutkowski, J. M., & Scherer, P. E. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.011 · Cited by 1,031 · see citing works
Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells
Olofsson, C. S., Göpel, S. O., Barg, S., Galvanovskis, J., Ma, X., Salehi, A., Rorsman, P., & Eliasson, L. (2002) · Pflügers Archiv · doi:10.1007/s00424-002-0781-5 · Cited by 290 · see citing works
Self-citationGlucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells
Ravier, M. A., & Rutter, G. A. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1789 · Cited by 264 · see citing works
Reversible changes in pancreatic islet structure and function produced by elevated blood glucose
Brereton, M. F., Iberl, M., Shimomura, K., Zhang, Q., Adriaenssens, A. E., Proks, P., Spiliotis, I. I., Dace, W., Mattis, K. K., Ramracheya, R., et al. (2014) · Nature Communications · doi:10.1038/ncomms5639 · Cited by 259 · see citing works
Self-citationZhang, Q., Ramracheya, R., Lahmann, C., Tarasov, A., Bengtsson, M., Braha, O., Braun, M., Brereton, M., Collins, S., Galvanovskis, J., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.014 · Cited by 225 · see citing works
Self-citationGlucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells
Vieira, E., Salehi, A., & Gylfe, E. (2007) · Diabetologia · doi:10.1007/s00125-006-0511-1 · Cited by 218 · see citing works
Gromada, J., Ma, X., Høy, M., Bokvist, K., Salehi, A., Berggren, P.-O., & Rorsman, P. (2004) · Diabetes · doi:10.2337/diabetes.53.suppl_3.s181 · Cited by 164 · see citing works
Self-citationGöpel, S., Zhang, Q., Eliasson, L., Ma, X., Galvanovskis, J., Kanno, T., Salehi, A., & Rorsman, P. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2003.059675 · Cited by 160 · see citing works
Self-citationParadoxical Stimulation of Glucagon Secretion by High Glucose Concentrations
Salehi, A., Vieira, E., & Gylfe, E. (2006) · Diabetes · doi:10.2337/db06-0080 · Cited by 159 · see citing works
Olsen, H. L., Theander, S., Bokvist, K., Buschard, K., Wollheim, C. B., & Gromada, J. (2005) · Endocrinology · doi:10.1210/en.2005-0800 · Cited by 156 · see citing works
Self-citationRamracheya, R., Ward, C., Shigeto, M., Walker, J. N., Amisten, S., Zhang, Q., Johnson, P. R., Rorsman, P., & Braun, M. (2010) · Diabetes · doi:10.2337/db09-1505 · Cited by 136 · see citing works
Self-citationRamracheya, R., Chapman, C., Chibalina, M., Dou, H., Miranda, C., González, A., Moritoh, Y., Shigeto, M., Zhang, Q., Braun, M., et al. (2018) · Physiological Reports · doi:10.14814/phy2.13852 · Cited by 128 · see citing works
Self-citationLiu, Y.-J., Vieira, E., & Gylfe, E. (2004) · Cell Calcium · doi:10.1016/j.ceca.2003.10.002 · Cited by 118 · see citing works
de Heer, J., & Holst, J. J. (2007) · Diabetes · doi:10.2337/db06-0738 · Cited by 115 · see citing works
Glucagon secretion from pancreatic α-cells
Briant, L., Salehi, A., Vergari, E., Zhang, Q., & Rorsman, P. (2016) · Upsala Journal of Medical Sciences · doi:10.3109/03009734.2016.1156789 · Cited by 109 · see citing works
Self-citationGustavsson, N., Wei, S., Hoang, D. N., Lao, Y., Zhang, Q., Radda, G. K., Rorsman, P., Südhof, T. C., & Han, W. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.168005 · Cited by 100 · see citing works
Self-citationZhang, Q., Chibalina, M. V., Bengtsson, M., Groschner, L. N., Ramracheya, R., Rorsman, N. J. G., Leiss, V., Nassar, M. A., Welling, A., Gribble, F. M., et al. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.274209 · Cited by 90 · see citing works
Self-citationCell coupling in mouse pancreatic β-cells measured in intact islets of Langerhans
Zhang, Q., Galvanovskis, J., Abdulkader, F., Partridge, C. J., Göpel, S. O., Eliasson, L., & Rorsman, P. (2008) · Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences · doi:10.1098/rsta.2008.0110 · Cited by 80 · see citing works
Self-citationPedersen, M. G., Ahlstedt, I., El Hachmane, M. F., & Göpel, S. O. (2016) · Scientific Reports · doi:10.1038/srep31214 · Cited by 64 · see citing works
Self-citationCFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells
Edlund, A., Pedersen, M. G., Lindqvist, A., Wierup, N., Flodström-Tullberg, M., & Eliasson, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-00098-8 · Cited by 63 · see citing works
Alpha cell dysfunction in type 1 diabetes
Yosten, G. L. C. (2018) · Peptides · doi:10.1016/j.peptides.2017.12.001 · Cited by 62 · see citing works
Functional 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
Self-citationHussain, K., Bryan, J., Christesen, H. T., Brusgaard, K., & Aguilar-Bryan, L. (2005) · Diabetes · doi:10.2337/diabetes.54.10.2946 · Cited by 54 · see citing works
Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects
Dhalla, A. K., Yang, M., Ning, Y., Kahlig, K. M., Krause, M., Rajamani, S., & Belardinelli, L. (2014) · Diabetes · doi:10.2337/db13-1562 · Cited by 53 · see citing works
Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion
Watts, M., & Sherman, A. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2013.11.4504 · Cited by 45 · see citing works
Impaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor
Shiota, C., Rocheleau, J. V., Shiota, M., Piston, D. W., & Magnuson, M. A. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00102.2005 · Cited by 44 · see citing works
TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion
Dadi, P. K., Luo, B., Vierra, N. C., & Jacobson, D. A. (2015) · Molecular Endocrinology · doi:10.1210/me.2014-1321 · Cited by 40 · see citing works
Montefusco, F., & Pedersen, M. G. (2015) · The Journal of Physiology · doi:10.1113/jp270777 · Cited by 35 · see citing works
Grubelnik, V., Markovič, R., Lipovšek, S., Leitinger, G., Gosak, M., Dolenšek, J., Valladolid-Acebes, I., Berggren, P.-O., Stožer, A., Perc, M., et al. (2020) · Royal Society Open Science · doi:10.1098/rsos.191171 · Cited by 32 · see citing works
Modelling of energy-driven switch for glucagon and insulin secretion
Grubelnik, V., Zmazek, J., Markovič, R., Gosak, M., & Marhl, M. (2020) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2020.110213 · Cited by 15 · see citing works
Heterogeneous alpha-cell population modeling of glucose-induced inhibition of electrical activity
Montefusco, F., Cortese, G., & Pedersen, M. G. (2020) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2019.110036 · Cited by 13 · see citing works
A 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
- Authors
- Göpel, S. O., Kanno, T., Barg, S., Weng, X. ‐., Gromada, J., & Rorsman, P.
- Affiliations
- Lund University (SE)
- Novo Nordisk (Denmark) (DK)
- Corresponding author
- Rorsman, P.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2000-11
- Volume
- 528
- Issue
- 3
- Pages
- 509-520
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC2270147
- OpenAlex
- W2095268130
- Cited by
- 229
- References
- 25
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 11 · 2014: 16 · 2013: 9 · 2012: 9
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Lunds Universitet
- China Scholarship Council
- Hirosaki University
- Novo Nordisk Fonden
- 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
- glucagon secretion, alpha cells, ATP-sensitive potassium channels, tolbutamide, L-type Ca2+ channels, A-current, voltage-dependent inactivation, diazoxide, membrane potential, action potential generation, pancreatic islets
- MeSH terms
- Adenosine Triphosphate, Animals, Drug Resistance, Electrophysiology, Glucagon, Homeostasis, Islets of Langerhans, Tetrodotoxin, Calcium Channels, Potassium Channels, Sodium Channels, Ion Channel Gating, Tetraethylammonium, Sodium Channel Blockers, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
