The Journal of Membrane Biology

, Volume 197, Issue 2, pp 101–112

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

Article

DOI: 10.1007/s00232-003-0645-8

Cite this article as:
Zheng, Z., Wang, Z. & Delbono, O. J. Membrane Biol. (2004) 197: 101. doi:10.1007/s00232-003-0645-8

Abstract

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.

Keywords

Skeletal muscle Dihydropyridine receptor IGF-1 CREB CaM Kinase Calcineurin Calcium channels Gene transcription 

Copyright information

© Springer-Verlag New York Inc. 2004

Authors and Affiliations

  1. 1.Department of Physiology and PharmacologyWake Forest University School of Medicine, Winston-Salem, NC 27157USA
  2. 2.Department of Internal MedicineGerontology Wake Forest University School of Medicine, Winston-Salem, NC 27157USA
  3. 3.Neuroscience ProgramWake Forest University School of Medicine, Winston-Salem, NC 27157USA

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