Cx36-Mediated Coupling Reduces β-Cell Heterogeneity, Confines the Stimulating Glucose Concentration Range, and Affects Insulin Release Kinetics
Open accessAbstract
We studied the effect of gap junctional coupling on the excitability of β-cells in slices of pancreas, which provide a normal environment for islet cells. The electrophysiological properties of β-cells from mice (C57Bl/6 background) lacking the gap junction protein connexin36 (Cx36−/−) were compared with heterozygous (Cx36+/−) and wild-type littermates (Cx36+/+) and with frequently used wild-type NMRI mice. Most electrophysiological characteristics of β-cells were found to be unchanged after the knockout of Cx36, except the density of Ca2+ channels, which was increased in uncoupled cells. With closed ATP-sensitive K+ (KATP) channels, the electrically coupled β-cells of Cx36+/+ and Cx36+/− mice were hyperpolarized by the membrane potential of adjacent, inactive cells. Additionally, the hyperpolarization of one β-cell could attenuate or even stop the electrical activity of nearby coupled cells. In contrast, β-cells of Cx36−/− littermates with blocked KATP channels rapidly depolarized and exhibited a continuous electrical activity. Absence of electrical coupling modified the electrophysiological properties of β-cells consistent with the reported increase in basal insulin release and altered the switch on/off response of β-cells during an acute drop of the glucose concentration. Our data indicate an important role for Cx36-gap junctions in modulating stimulation threshold and kinetics of insulin release.
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The resting conductance is reduced by more than 80% (to 0.2 nS) in connexin36 KO islets, a value similar to that observed in isolated β-cells (0.1-0.2 nS).
“In support of this idea, the resting conductance is reduced by >80% (to 0.2 nS) in connexin36 KO islets (639), a value similar to that observed in isolated β-cells (0.1-0.2 nS)”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [639]
In the electrophysiology results (page unavailable), conductance falls from 1.2 nS in wild-type β-cells to 0.2 nS in Cx36 knockout β-cells—an approximately 83% reduction—and the knockout value is similar to the 0.22 nS reported for isolated β-cells. However, these are residual conductances measured after KATP channels were closed, not resting conductances; the paper says KATP channels account for most conductance under resting conditions. (LLM, conf=0.86)
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Ravier, M. A., Güldenagel, M., Charollais, A., Gjinovci, A., Caille, D., Söhl, G., Wollheim, C. B., Willecke, K., Henquin, J.-C., & Meda, P. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1798 · Cited by 360 · see citing works
Self-citationVoltage‐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
Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.
Barg, S., Galvanovskis, J., Göpel, S. O., Rorsman, P., & Eliasson, L. (2000) · Diabetes · doi:10.2337/diabetes.49.9.1500 · Cited by 209 · see citing works
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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
Connexins: Key Mediators of Endocrine Function
Bosco, D., Haefliger, J.-A., & Meda, P. (2011) · Physiological Reviews · doi:10.1152/physrev.00027.2010 · Cited by 169 · see citing works
Self-citationBenninger, R. K. P., Head, W. S., Zhang, M., Satin, L. S., & Piston, D. W. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.218909 · Cited by 165 · see citing works
δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin
Briant, L. J. B., Reinbothe, T. M., Spiliotis, I., Miranda, C., Rodriguez, B., & Rorsman, P. (2018) · The Journal of Physiology · doi:10.1113/jp274581 · Cited by 155 · see citing works
The Fractalkine/CX3CR1 System Regulates β Cell Function and Insulin Secretion
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Nguyen, L. M., Pozzoli, M., Hraha, T. H., & Benninger, R. K. P. (2014) · Diabetes · doi:10.2337/db13-1048 · Cited by 23 · see citing works
- Authors
- Speier, S., Gjinovci, A., Charollais, A., Meda, P., & Rupnik, M.
- Affiliations
- European Neuroscience Institute Göttingen (DE)
- University of Geneva (CH)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2007-04-01
- Volume
- 56
- Issue
- 4
- Pages
- 1078-1086
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2160109462
- Cited by
- 166
- References
- 3
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 11 · 2021: 12 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 13 · 2016: 3 · 2015: 10 · 2014: 17 · 2013: 14 · 2012: 13
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK63443, R01DK063443)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- connexin 36, electrical coupling, pancreatic beta cells, beta-cell heterogeneity, ATP-sensitive potassium channels
- MeSH terms
- Insulin Secretion, Gap Junction delta-2 Protein, Animals, Electrophysiology, Glucose, Insulin, Kinetics, Membrane Potentials, Mice, Inbred Strains, Connexins, Mice, Knockout, Patch-Clamp Techniques, Insulin-Secreting Cells, Mice
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