Loss of Connexin36 Channels Alters β-Cell Coupling, Islet Synchronization of Glucose-Induced Ca2+ and Insulin Oscillations, and Basal Insulin Release
Abstract
Normal insulin secretion requires the coordinated functioning of β-cells within pancreatic islets. This coordination depends on a communications network that involves the interaction of β-cells with extracellular signals and neighboring cells. In particular, adjacent β-cells are coupled via channels made of connexin36 (Cx36). To assess the function of this protein, we investigated islets of transgenic mice in which the Cx36 gene was disrupted by homologous recombination. We observed that compared with wild-type and heterozygous littermates that expressed Cx36 and behaved as nontransgenic controls, mice homozygous for the Cx36 deletion (Cx36−/−) featured β-cells devoid of gap junctions and failing to exchange microinjected Lucifer yellow. During glucose stimulation, islets of Cx36−/− mice did not display the regular oscillations of intracellular calcium concentrations ([Ca2+]i) seen in controls due to the loss of cell-to-cell synchronization of [Ca2+]i changes. The same islets did not release insulin in a pulsatile fashion, even though the overall output of the hormone in response to glucose stimulation was normal. However, under nonstimulatory conditions, islets lacking Cx36 showed increased basal release of insulin. These data show that Cx36-dependent signaling is essential for the proper functioning of β-cells, particularly for the pulsatility of [Ca2+]i and insulin secretion during glucose stimulation.
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In connexin-36 KO mice, synchronized [Ca2+]i oscillations are no longer observed at the whole-islet level.
“and in connexin-36 KO mice, synchronized [Ca2+]i oscillations are no longer observed at the whole-islet level (537).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [537]
Connexin-36 (Gjd2/GJD2) is the only connexin expressed at significant levels in either mouse or human islets.
“Connexin-36 (Gjd2/GJD2) is the only connexin expressed at significant levels in either mouse or human islets (Appendix Figure 10), and in connexin-36 KO mice, synchronized [Ca2+]i oscillations are no longer observed at the whole-islet level (537).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [537]
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- Authors
- Ravier, M. A., Güldenagel, M., Charollais, A., Gjinovci, A., Caille, D., Söhl, G., Wollheim, C. B., Willecke, K., Henquin, J.-C., & Meda, P.
- Affiliations
- UCLouvain (BE)
- Institute of Genetics, University of Bonn, Bonn, Germany
- University of Geneva (CH)
- Department of Cell Physiology and Metabolism, Geneva University Medical Center, Geneva, Switzerland
- University of Bonn (DE)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-06-01
- Volume
- 54
- Issue
- 6
- Pages
- 1798-1807
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2108896758
- Cited by
- 360
- References
- 52
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 12 · 2023: 19 · 2022: 20 · 2021: 28 · 2020: 19 · 2019: 12 · 2018: 10 · 2017: 19 · 2016: 18 · 2015: 19 · 2014: 26 · 2013: 24 · 2012: 25
- FWCI
- 16.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK63443, R01DK063443)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- connexin 36, gap junctions, pancreatic islets, insulin secretion, calcium oscillations, insulin oscillations, glucose-stimulated insulin secretion
- MeSH terms
- Gap Junction delta-2 Protein, Animals, Calcium, Female, Glucose, Heterozygote, Homozygote, Insulin, Islets of Langerhans, Male, Connexins, Mice, Knockout, Mice
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