β-cell CaV channel regulation in physiology and pathophysiology

The beta-cell is equipped with at least six voltage-gated Ca2+ (Ca-V) channel alpha(1)-subunits designated Ca(V)1.2, Ca(V)1.3, Ca(V)2.1, Ca(V)2.2, Ca(V)2.3, and Ca(V)3.1. These principal subunits, together with certain auxiliary subunits, assemble into different types of Ca-V channels conducting L-, P/Q-, N-, R-, and T-type Ca2+ currents, respectively. The beta-cell shares customary mechanisms of CaV channel regulation with other excitable cells, such as protein phosphorylation, Ca2+-dependent inactivation, and G protein modulation. However, the beta-cell displays some characteristic features to bring these mechanisms into play. In islet beta-cells, CaV channels can be highly phosphorylated under basal conditions and thus marginally respond to further phosphorylation. In beta-cell lines, CaV channels can be surrounded by tonically activated protein phosphatases dominating over protein kinases; thus their activity is dramatically enhanced by inhibition of protein phosphatases. During the last 10 years, we have revealed some novel mechanisms of beta-cell CaV channel regulation under physiological and pathophysiological conditions, including the involvement of exocytotic proteins, inositol hexakisphosphate, and type 1 diabetic serum. This minireview highlights characteristic features of customary mechanisms of CaV channel regulation in beta-cells and also reviews our studies on newly identified mechanisms of beta-cell CaV channel regulation.