The role of voltage-gated calcium channels in pancreatic β-cell physiology and pathophysiology

Voltage-gated calcium (Ca-V) channels are ubiquitously expressed in various cell types throughout the body. In principle, the molecular identity, biophysical profile, and pharmacological property of CaV channels are independent of the cell type where they reside, whereas these channels execute unique functions in different cell types, such as muscle contraction, neurotransmitter release, and hormone secretion. At least six Ca-V alpha(1) subunits, including 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, have been identified in pancreatic beta-cells. These pore-forming subunits complex with certain auxiliary subunits to conduct L-, P/Q-, N-, R-, and T-type CaV currents, respectively. beta-Cell CaV channels take center stage in insulin secretion and play an important role in beta-cell physiology and pathophysiology. Ca(V)3 channels become expressed in diabetes-prone mouse beta-cells. Point mutation in the human Ca(V)1.2 gene results in excessive insulin secretion. Trinucleotide expansion in the human Ca(V)1.3 and Ca(V)2.1 gene is revealed in a subgroup of patients with type 2 diabetes. beta-Cell Ca-V channels are regulated by a wide range of mechanisms, either shared by other cell types or specific to beta-cells, to always guarantee a satisfactory concentration of Ca2+. Inappropriate regulation of beta-cell Ca-V channels causes beta-cell dysfunction and even death manifested in both type 1 and type 2 diabetes. This review summarizes current knowledge of Ca-V channels in beta-cell physiology and pathophysiology.