Loss of Connexin36 Channels Alters β-Cell Coupling, Islet Synchronization of Glucose-Induced Ca2+ and Insulin Oscillations, and Basal Insulin Release

  1. Magalie A. Ravier1,
  2. Martin Güldenagel2,
  3. Anne Charollais3,
  4. Asllan Gjinovci3,
  5. Dorothée Caille3,
  6. Goran Söhl2,
  7. Claes B. Wollheim3,
  8. Klaus Willecke2,
  9. Jean-Claude Henquin1 and
  10. Paolo Meda3
  1. 1Unit of Endocrinology and Metabolism, University of Louvain Faculty of Medicine, Brussels, Belgium
  2. 2Institute of Genetics, University of Bonn, Bonn, Germany
  3. 3Department of Cell Physiology and Metabolism, Geneva University Medical Center, Geneva, Switzerland
  1. Address correspondence and reprint requests to Paolo Meda, MD, Department of Cell Physiology and Metabolism, University of Geneva, C.M.U., 1 rue Michel Servet, 1211 Geneva 4, Switzerland. E-mail: paolo.meda{at}medecine.unige.ch. Jean-Claude Henquin, Unit of Endocrinology and Metabolism, University of Louvain Faculty of Medicine, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium. E-mail: henquin{at}endo.ucl.ac.be

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.

Footnotes

  • M.A.R., M.G., and A.C. contributed equally to this work.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 11, 2005.
    • Received December 8, 2004.
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