Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice |
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| Authors: | Schulla Verena Renström Erik Feil Robert Feil Susanne Franklin Isobel Gjinovci Asllan Jing Xing-Jun Laux Dirk Lundquist Ingmar Magnuson Mark A Obermüller Stefanie Olofsson Charlotta S Salehi Albert Wendt Anna Klugbauer Norbert Wollheim Claes B Rorsman Patrik Hofmann Franz |
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| Affiliation: | Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Strasse 29, D-80802 München, Germany. |
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| Abstract: | Insulin is secreted from pancreatic beta cells in response to an elevation of cytoplasmic Ca(2+) resulting from enhanced Ca(2+) influx through voltage-gated Ca(2+) channels. Mouse beta cells express several types of Ca(2+) channel (L-, R- and possibly P/Q-type). beta cell-selective ablation of the gene encoding the L-type Ca(2+) channel subtype Ca(v)1.2 (betaCa(v)1.2(-/-) mouse) decreased the whole-cell Ca(2+) current by only approximately 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 Ca(2+) 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 betaCa(v)1.2(-/-) mouse was associated with the disappearance of a rapid component of exocytosis reflecting fusion of secretory granules physically attached to the Ca(v)1.2 channel. Thus, the conduit of Ca(2+) entry determines the ability of the cation to elicit secretion. |
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