Impaired insulin secretion and glucose tolerance in β cell-selective CaV1.2 Ca2+ channel null mice

Insulin is secreted from pancreatic beta cells in response to an elevation of cytoplasmic Ca2+ resulting from enhanced Ca2+ influx through voltage-gated Ca2+ channels. Mouse beta cells express several types of Ca2+ channel (L-, R- and possibly P/Q-type). beta cell-selective ablation of the gene encoding the L-type Ca2+ channel subtype Ca(v)1.2 (betaCa(v)1.2(-/-) mouse) decreased the whole-cell Ca2+ current by only similar to45%, but almost abolished first-phase insulin secretion and resulted in systemic glucose intolerance. These effects did not correlate with any major effects on intracellular Ca2+ 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 Ca2+ entry determines the ability of the cation to elicit secretion.