Figure 2.

Role of the HVCC subunits on pancreatic β-cell insulin release. (A). Localization of the HVCC isoforms in pancreatic β-cells with respect to insulin vesicles. At least in mouse, Ca_V1.2 channels are coupled to vesicle release, while evidence suggests that in human β-cells, Ca_V2.1 takes the central role. The localization of Ca_V1.2 channels at the release sites is controlled by the interaction between β₂ subunit and ELKS. Ca_V2.3 channels are necessary for sustained insulin release, while the role of Ca_V1.3 is very controversial. β3 isoform does not come in complex with any HVCC but interacts with the IP₃R. (B) Effect of genetic deletion or pharmacological block of each HVCC subunit isoform on total β-cell Ca²⁺ current. Ca_V1.2 contribute with ~45% of the whole-cell Ca²⁺ influx while Ca_V2.1 and Ca_V2.3 with ~20% each. Ca_V1.3 deletion only shifts the voltage dependence of activation. α₂δ-1 deletion reduces all HVCC Ca²⁺ currents by ~70% while γ₄ altered expression reduces only L-type Ca²⁺ currents (~70%). (C) Role of the HVCC subunits on GIIS. Ca_V1.2 deletion has the strongest effect as it is coupled to insulin vesicle release. Ca_V1.3 deletion reduces insulin secretion at lower glucose concentration while lack of Ca_V2.3 Ca²⁺ currents reduces second-phase GIIS. α₂δ-1 deletion strongly reduces GIIS, while β₃ deletion increases insulin release. γ₄ reduced expression is expected to have similar effects as Ca_V1.2 deletion.