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  • The EMBO Journal (2003) 22, 3844 - 3854
  • doi:10.1093/emboj/cdg389

Impaired insulin secretion and glucose tolerance in bold beta cell-selective CaV1.2 Ca2+ channel null mice

Verena Schulla1, Erik Renström2, Robert Feil1, Susanne Feil1, Isobel Franklin3, Asllan Gjinovci3, Xing-Jun Jing2, Dirk Laux1, Ingmar Lundquist2, Mark A. Magnuson4, Stefanie Obermüller2, Charlotta S. Olofsson2, Albert Salehi2, Anna Wendt2, Norbert Klugbauer1, Claes B. Wollheim3, Patrik Rorsman2 and Franz Hofmann1

  1. Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Strasse 29, D-80802 München, Germany
  2. Department of Physiological Sciences, Lund University, BMC F11, SE-221 84 Lund, Sweden
  3. Division of Clinical Biochemistry, University Medical Center, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland
  4. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

Correspondence to:

Erik Renström, E-mail: erik.renstrom@mphy.lu.se

Received 2 February 2003; Accepted 16 June 2003; Revised 15 May 2003

Insulin is secreted from pancreatic beta cells in response to an elevation of cytoplasmic Ca2+ resulting from enhanced Ca2+ influx through voltage-gated Ca2+ channels. Mouse beta cells express several types of Ca2+ channel (L-, R- and possibly P/Q-type). beta cell-selective ablation of the gene encoding the L-type Ca2+ channel subtype Cav1.2 (betaCav1.2-/- mouse) decreased the whole-cell Ca2+ current by only approx45%, but almost abolished first-phase insulin secretion and resulted in systemic glucose intolerance. These effects did not correlate with any major effects on intracellular Ca2+ handling and glucose-induced electrical activity. However, high-resolution capacitance measurements of exocytosis in single beta cells revealed that the loss of first-phase insulin secretion in the betaCav1.2-/- mouse was associated with the disappearance of a rapid component of exocytosis reflecting fusion of secretory granules physically attached to the Cav1.2 channel. Thus, the conduit of Ca2+ entry determines the ability of the cation to elicit secretion.

  • Keywords:

    • Ca2+ channels,
    • diabetes,
    • exocytosis,
    • insulin secretion,
    • pancreatic beta cells