The ablation of the Ca(v)2.3/E-type voltage-gated Ca2+ channel causes a mild phenotype despite an altered glucose induced glucagon response in isolated islets of Langerhans.

Glucagon release upon hypoglycemia is an important homeostatic mechanism utilized by vertebrates to restore blood glucose to normal. Glucagon secretion itself is triggered by Ca2+ influx through voltage-gated ion channels, and the gene inactivation of R-type Ca2+ channels, with Ca(v)2.3 as the ion conducting subunit, has been shown to disturb glucose homeostasis. To understand how glucagon release may be affected in Ca(v)2.3-deficient mice, carbachol, insulin and glucose induced glucagon response was investigated. While the rise of insulin and glucose induced by carbachol is normal, mutant mice show an impaired glucagon-response. Further, the effect of insulin injection on glucagon levels was altered by the loss of the Ca(v)2.3 subunit. Ca(v)2.3-deficient mice are characterized by an impaired glucose suppression of glucagon release. This was most obvious at the level of isolated islets suggesting that Ca(v)2.3 containing R-type voltage-gated Ca2+ channels are involved in the glucose-mediated signalling to glucagon release in mice.

Disturbances in glucose-tolerance, insulin-release, and stress-induced hyperglycemia upon disruption of the Ca(v)2.3 (alpha 1E) subunit of voltage-gated Ca(2+) channels.

Multiple types of voltage-activated Ca(2+) channels (T, L, N, P, Q, R type) coordinate Ca(2+)-dependent processes in neurons and neuroendocrine cells. Expressional and functional data have suggested a role for Ca(v)2.3 Ca(2+) channels in endocrine processes. To verify its role in vivo, Ca(v)2.3(-/-) mutant mice were generated, thus deficient in alpha 1E/R-type Ca(2+) channel. Intraperitoneal injection of D-glucose showed that glucose tolerance was markedly reduced, and insulin release into plasma was impaired in Ca(v)2.3-deficient mice. In isolated islets of Langerhans from these animals, no glucose-induced insulin release was detected. Further, in stressed Ca(v)2.3-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(v)2.3 causes deficits not only in insulin release but also in stress-induced hyperglycemia. The complex phenotype of Ca(v)2.3-deficient mice has dual components related to endocrine and neurological defects. The present findings provide direct evidence of a functional role for the Ca(v)2.3 subunit in hormone secretion and glucose homeostasis.