Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice

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 g...

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Published in:The EMBO journal 2003-08, Vol.22 (15), p.3844-3854
Main 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
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Calcium Channels, L-Type - genetics
Calcium Channels, L-Type - physiology
DNA Primers
Exocytosis
Insulin - metabolism
Insulin Resistance
Insulin Secretion
Islets of Langerhans - metabolism
Islets of Langerhans - physiology
Mice
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Summary: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.
ISSN:0261-4189
DOI:10.1093/emboj/cdg389