CACN4, THE MAJOR ALPHA-1 SUBUNIT ISOFORM OF VOLTAGE-DEPENDENT CALCIUMCHANNELS IN PANCREATIC BETA-CELLS - A MINIREVIEW OF CURRENT PROGRESS

Calcium influx through L-type voltage-dependent calcium channels (VDCC s) triggers insulin secretion. Until recently, the structure of VDCCs in pancreatic beta-cells and their regulation in altered metabolic sta tes were not known. Study of the VDCC protein in skeletal muscle has s hown that the alpha 1 subunit is functionally the most important subun it among the five subuints (alpha 1, alpha 2, beta, gamma and delta), acting as a voltage sensor and an ion-conducting pore. Molecular cloni ng of a novel alpha 1 subunit (beta-cell/neuroendocrine type, CACN4) o f VDCCs from pancreatic islets and insulinoma have made it possible to study the electrophysiological and pharmacogical properties, regulati on, and genetics of the VDCCs expressed in beta-cells. The CACN4 is st ructurally related to other members of the VDCC alpha 1 subunit family , including skeletal muscle, cardiac, and brain types. In situ hybridi zation experiments reveal that CACN4 mRNAs are expressed in beta-cells in the islets. Heterologous expession studies show that CACN4 in the presence of the beta subunit elicits L-type VDCC currents, although ex pression of CACN4 alone is not sufficient for VDCC acitivity. Studies of animal models with chronic hyperglycemia and starvation have indica ted that the reduced CACN4 mRNA levels in pancreatic islets are associ ated 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 al tered metabolic states.