Disturbances in glucose-tolerance, insulin-release, and stress-induced hyperglycemia upon disruption of the Ca(V)2.3 (alpha 1E) subunit of voltage-gated Ca2+ channels

Abstract

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 Cav2.3 Ca2+ channels in endocrine processes. To verify its role in vivo, Cav2.3(-/-) mutant mice were generated, thus deficient in {alpha}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 Cav2.3-deficient mice. In isolated islets of Langerhans from these animals, no glucose-induced insulin release was detected. Further, in stressed Cav2.3-deficient mice, the rate of glucose release into the blood was only 29% of that observed for wild-type animals. Thus, the deletion of Cav2.3 causes deficits not only in insulin release but also in stress-induced hyperglycemia. The complex phenotype of Cav2.3-deficient mice has dual components related to endocrine and neurological defects. The present findings provide direct evidence of a functional role for the Cav2.3 subunit in hormone secretion and glucose homeostasis