Voltage-gated Ca (Ca) 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 gamma subunit 4 (Caγ4) 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 Caγ4 expression results in decreased expression of L-type Ca1.2 and Ca1.3, thereby suppressing voltage-gated Ca entry and glucose stimulated insulin exocytosis. The most important finding is that Caγ4 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 ( ). Taken together, these findings suggest that Caγ4 is necessary for maintaining a functional differentiated beta-cell phenotype. Treatment aiming at restoring Caγ4 may help to restore beta-cell function in diabetes.
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| http://dx.doi.org/10.1038/s42003-019-0351-4 | DOI Listing |
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