CACN4, the major alpha 1 subunit isoform of voltage-dependent calcium channels in pancreatic beta-cells: a minireview of current progress.

Calcium influx through L-type voltage-dependent calcium channels (VDCCs) triggers insulin secretion. Until recently, the structure of VDCCs in pancreatic beta-cells and their regulation in altered metabolic states were not known. Study of the VDCC protein in skeletal muscle has shown that the alpha 1 subunit is functionally the most important subunit among the five subunits (alpha 1, alpha 2, beta, gamma and delta), acting as a voltage sensor and an ion-conducting pore. Molecular cloning of a novel alpha 1 subunit (beta-cell/neuroendocrine type, CACN4) of VDCCs from pancreatic islets and insulinoma have made it possible to study the electrophysiological and pharmacogical properties, regulation, and genetics of the VDCCs expressed in beta-cells. The CACN4 is structurally related to other members of the VDCC alpha 1 subunit family, including skeletal muscle, cardiac, and brain types. In situ hybridization experiments reveal that CACN4 mRNAs are expressed in beta-cells in the islets. Heterologous expression studies show that CACN4 in the presence of the beta subunit elicits L-type VDCC currents, although expression of CACN4 alone is not sufficient for VDCC activity. Studies of animal models with chronic hyperglycemia and starvation have indicated that the reduced CACN4 mRNA levels in pancreatic islets are associated with impaired insulin responses to stimuli in both hyperglycemic and fasting states. These studies demonstrate that CACN4 is the major component of VDCCs in pancreatic beta-cells and suggest that it plays a crucial role in the regulation of insulin secretion in normal and altered metabolic states.