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

Voltage-gated Ca2+ (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 gamma 4) 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 gamma 4 expression results in decreased expression of L-type Ca(V)1.2 and Ca(V)1.3, thereby suppressing voltage-gated Ca2+ entry and glucose stimulated insulin exocytosis. The most important finding is that Ca-V gamma 4 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(Delta beta cell)). Taken together, these findings suggest that Ca-V gamma 4 is necessary for maintaining a functional differentiated beta-cell phenotype. Treatment aiming at restoring Ca-V gamma 4 may help to restore beta-cell function in diabetes.