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| Subject Categories: Membranes & Transport | Molecular Biology of Disease |
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| The EMBO Journal
(2003) 22, 3844–3854, doi:10.1093/emboj/cdg389 |
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Impaired insulin secretion and glucose tolerance in  cell-selective CaV1.2 Ca2+ channel null mice |
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| 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 |
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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 To whom correspondence should be addressed Erik Renström, erik.renstrom@mphy.lu.se Received 2 February 2003; Revised 15 May 2003; Accepted 16 June 2003. |
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| Abstract |
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Insulin is secreted from pancreatic cells in response to an elevation of cytoplasmic Ca2+ resulting from enhanced Ca2+ influx through voltage-gated Ca2+ channels. Mouse cells express several types of Ca2+ channel (L-, R- and possibly P/Q-type). cell-selective ablation of the gene encoding the L-type Ca2+ channel subtype Cav1.2 (Cav1.2-/- mouse) decreased the whole-cell Ca2+ current by only  45%, 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 cells revealed that the loss of first-phase insulin secretion in the Cav1.2-/- 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. |
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| Keywords: Ca2+ channels, diabetes, exocytosis, insulin secretion, pancreatic cells |
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