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 Ca_V 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 _Vα₁ subunits, including Ca_V1.2, Ca _V1.3, Ca_V2.1, Ca_V2.2, Ca_V2.3, and Ca_V3.1, have been identified in pancreatic β-cells. These pore-forming subunits complex with certain auxiliary subunits to conduct L-, P/Q-, N-, R-, and T-type Ca_V currents, respectively. β-Cell Ca_V channels take center stage in insulin secretion and play an important role in β-cell physiology and pathophysiology. Ca_V3 channels become expressed in diabetes-prone mouse β-cells. Point mutation in the human Ca_V1.2 gene results in excessive insulin secretion. Trinucleotide expansion in the human Ca_V1.3 and Ca_V2.1 gene is revealed in a subgroup of patients with type 2 diabetes. β-Cell Ca_V channels are regulated by a wide range of mechanisms, either shared by other cell types or specific to β-cells, to always guarantee a satisfactory concentration of Ca²⁺. Inappropriate regulation of β-cell Ca_V channels causes β-cell dysfunction and even death manifested in both type 1 and type 2 diabetes. This review summarizes current knowledge of Ca_V channels in β-cell physiology and pathophysiology.