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Disturbances in Glucose-Tolerance, Insulin-Release, and Stress-Induced Hyperglycemia upon Disruption of the Ca_v2.3 (1E) Subunit of Voltage-Gated Ca²⁺ Channels

Institute of Neurophysiology (A.P., M.M., R.V., C.G., M.H., M.W., J.H., T.S.) and Institute of Biochemistry (N.S.), University of Cologne, D-50931 Köln, Germany

Address all correspondence and requests for reprints to: Toni Schneider, University of Cologne, Institute of Neurophysiology, Robert-Koch-Strasse 39, D-50931 Köln, Germany. E-mail: Toni.Schneider{at}uni-koeln.de.

Multiple types of voltage-activated Ca²⁺ channels (T, L, N, P, Q, R type) coordinate Ca²⁺-dependent processes in neurons and neuroendocrine cells. Expressional and functional data have suggested a role for Ca_v2.3 Ca²⁺ channels in endocrine processes. To verify its role in vivo, Ca_v2.3(-/-) mutant mice were generated, thus deficient in 1E/R-type Ca²⁺ channel. Intraperitoneal injection of D-glucose showed that glucose tolerance was markedly reduced, and insulin release into plasma was impaired in Ca_v2.3-deficient mice. In isolated islets of Langerhans from these animals, no glucose-induced insulin release was detected. Further, in stressed Ca_v2.3-deficient mice, the rate of glucose release into the blood was only 29% of that observed for wild-type animals. Thus, the deletion of Ca_v2.3 causes deficits not only in insulin release but also in stress-induced hyperglycemia. The complex phenotype of Ca_v2.3-deficient mice has dual components related to endocrine and neurological defects. The present findings provide direct evidence of a functional role for the Ca_v2.3 subunit in hormone secretion and glucose homeostasis.

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