Ca2+ Calmodulin Kinase and Calcineurin Mediate IGF-1-induced Skeletal Muscle Dihydropyridine Receptor α1S Transcription

Ca2+ Calmodulin Kinase and Calcineurin Mediate IGF-1-induced Skeletal Muscle Dihydropyridine... The skeletal muscle L-type Ca2+ channel or dihydropyridine(DHP)-sensitive receptor is a key molecule involved in membrane voltage-sensing, sarcoplasmic reticulum Ca2+ release, and muscle contraction. Previous work from our laboratory has shown that the insulin-like growth factor-1 (IGF-1) increases skeletal muscle L-type Ca2+ channel or dihydropyridine-sensitive receptor DHPRα1S transcriptional activity by acting on the cyclic AMP response element binding protein (CREB) element of the promoter region; however, the cellular signaling mediating this process is not known. In this study, we investigated the signaling pathway whereby IGF-1 enhances the expression of DHPRα1S in C2C12 myotubes, using a molecular, pharmacological and electrophysiological approach. We found that inhibition of the Ca2+/Calmodulin (CaM)-dependent protein kinase or calcineurin, influenced IGF-1-induced increase in DHPRα1S expression, as detected by recording the luminescence of the DHPRα1S promoter–luciferase fusion construct and by immunoblot analysis of the DHPR α1 subunit. IGF-1 significantly increased CaM kinase and calcineurin activity and the cellular levels of phosphorylated CREB in a time-dependent manner. The role of CaM kinase and calcineurin in DHPRα1S expression was confirmed by functional recording of the effects of the inhibition of the kinase and phosphatase on IGF-1-mediated enhancement of charge movement. These results support the conclusion that IGF-1 controls CREB phosphorylation by activating a phosphorylation and dephosphorylation cascade, which ultimately modulates the DHPRα1S gene transcription. The Journal of Membrane Biology Springer Journals

Ca2+ Calmodulin Kinase and Calcineurin Mediate IGF-1-induced Skeletal Muscle Dihydropyridine Receptor α1S Transcription

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Copyright © 2004 by Springer-Verlag New York Inc.
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