The calcium channel subunit gamma-4 is regulated by MafA and necessary for pancreatic beta-cell specification

Voltage-gated Ca(2+) (Ca(V)) channels trigger glucose-induced insulin secretion in pancreatic beta-cell and their dysfunction increases diabetes risk. These heteromeric complexes include the main subunit alpha1, and the accessory ones, including subunit gamma that remains unexplored. Here, we demonstrate that Ca(V) gamma subunit 4 (Ca(V)γ4) is downregulated in islets from human donors with diabetes, diabetic Goto-Kakizaki (GK) rats, as well as under conditions of gluco-/lipotoxic stress. Reduction of Ca(V)γ4 expression results in decreased expression of L-type Ca(V)1.2 and Ca(V)1.3, thereby suppressing voltage-gated Ca(2+) entry and glucose stimulated insulin exocytosis. The most important finding is that Ca(V)γ4 expression is controlled by the transcription factor responsible for beta-cell specification, MafA, as verified by chromatin immunoprecipitation and experiments in beta-cell specific MafA knockout mice (MafA(Δβcell)). Taken together, these findings suggest that Ca(V)γ4 is necessary for maintaining a functional differentiated beta-cell phenotype. Treatment aiming at restoring Ca(V)γ4 may help to restore beta-cell function in diabetes.