期刊
COMMUNICATIONS BIOLOGY
卷 2, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-019-0351-4
关键词
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资金
- Swedish Research Council, Strategic Research Area Exodiab [2009-1039]
- Swedish Foundation for Strategic Research [IRC 15-0067]
- Swedish Research Council [349-2006-237]
- Diabetes Wellness foundation
- Swedish Research Council
- Juvenile Diabetes Research Foundation
- Diabetesfonden
- Crafoord foundation
- European Foundation for the Study of Diabetes
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.
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