β-cell Ca_v channel regulation in physiology and pathophysiology

The β-cell is equipped with at least six voltage-gated Ca²⁺ (Ca_v) channel α₁-subunits designated Ca _v1.2, Ca_v1.3, Ca_v2.1, Ca_v2.2, Ca_v2.3, and Ca_v3.1. 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 β-cell shares customary mechanisms of Ca_v channel regulation with other excitable cells, such as protein phosphorylation, Ca²⁺-dependent inactivation, and G protein modulation. However, the β-cell displays some characteristic features to bring these mechanisms into play. In islet β-cells, Ca_v channels can be highly phosphorylated under basal conditions and thus marginally respond to further phosphorylation. In β-cell lines, Ca_v 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 β-cell Ca_v 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 Ca_v channel regulation in β-cells and also reviews our studies on newly identified mechanisms of β-cell Ca_v channel regulation.