Disturbances in Glucose-Tolerance, Insulin-Release, and Stress-Induced Hyperglycemia upon Disruption of the Ca_v2.3 (α1E) Subunit of Voltage-Gated Ca²⁺Channels

Abstract

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.

Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

“…Finally, we examined the role of R-type VGCCs in the observed regulation using both pharmacological blockade by SNX-482, and by the genetic ablation of the ␣1E channel subunit in mice (31). In both these models, the inhibition of glutamate release by muscimol was abolished.…”

“…Preparation of Synaptosomes-Percoll gradient-purified synaptosomes were prepared as described previously (30) from the cerebral cortices of 2-month-old male Sprague-Dawley rats or from male wild-type or R-type (Ca V 2.3) ␣1E subunit-deficient (␣1E Ϫ/Ϫ ) mutant mice characterized previously (31). On incubation at 37°C, synaptosomes show metabolic competence and ability to release neurotransmitters (32,33).…”

“…To authenticate the role of R-type VGCCs in the observed modulation of glutamate release by muscimol, we carried out experiments utilizing synaptosomes prepared from the neocortex of ␣1E subunit knock-out (␣1E Ϫ/Ϫ ) mice lacking the R-type VGCC activity (31). In wild-type mice, glutamate release evoked by 1 mM 4AP under control conditions (35.5 Ϯ 1.3 nmol/mg/5 min) was significantly reduced by muscimol (200 M, 31.6 Ϯ 0.4 nmol/mg/5 min, 89% of control release in wildtype mice; Fig.…”

Arrhythmia in Isolated Prenatal Hearts after Ablation of the Ca_v2.3 (α1E) Subunit of Voltage-gated Ca²⁺ Channels

“…Furthermore, Ca v 2.3 deficient mice also develop a phenotype related to defects in the endocrine system and to various other functions [7][8][9]. The expression of Ca v 2.3 in heart was reported but is still under discussion.…”

Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo

“…Homozygous littermates are regularly interbred with each other and back-bred into C57Bl/6 (for further information on knock out generation see [10, 11]. Mice were kept at 20°C in makrolon type II cages under a 12h light-dark cycle (7: 00 a.m./p.m.)…”