Calmodulin regulation of excitation-contraction coupling in cardiac myocytes.

Journal Article (Journal Article)

Calmodulin (CaM) as a ubiquitous Ca2+ sensor interacts with multiple key molecules involved in excitation-contraction (EC) coupling. In the present study, we report that adenoviral expression of a mutant CaM lacking all of its four Ca2+-binding sites, CaM(1-4), at a level 6.5-fold over endogenous CaM markedly increases the amplitude and abbreviates the decay time of Ca2+ transients and contraction in cultured rat ventricular myocytes. To determine the underlying mechanisms, we examined the properties of L-type Ca2+ channels, Ca2+/CaM-dependent protein kinase II (CaMKII), and phospholamban (PLB) in the sarcoplasmic reticulum (SR). We found that CaM(1-4) expression markedly augmented L-type Ca2+ current amplitude and slowed its inactivation. Surprisingly, overexpression of CaM(1-4) increased CaMKII activity and phosphorylation of PLB-Thr-17. Moreover, CaM(1-4) elevated diastolic Ca2+ and caffeine-labile Ca2+ content of the SR. Inhibition of CaMKII by KN-93 or a myristoylated autocamtide-2 related inhibitory peptide prevented the aforementioned PLB phosphorylation and reversed the positive inotropic and relaxant effects, indicating that CaMKII is essential to CaM(1-4) actions. These results demonstrate that CaM modulates Ca2+ influx, SR Ca2+ release, and Ca2+ recycling during cardiac EC coupling. A novel finding of this study is that expression of a Ca2+-insensitive CaM mutant can lead to activation of CaMKII in cardiac myocytes.

Full Text

Duke Authors

Cited Authors

  • Yang, D; Song, L-S; Zhu, W-Z; Chakir, K; Wang, W; Wu, C; Wang, Y; Xiao, R-P; Chen, SRW; Cheng, H

Published Date

  • April 4, 2003

Published In

Volume / Issue

  • 92 / 6

Start / End Page

  • 659 - 667

PubMed ID

  • 12609973

Electronic International Standard Serial Number (EISSN)

  • 1524-4571

Digital Object Identifier (DOI)

  • 10.1161/01.RES.0000064566.91495.0C


  • eng

Conference Location

  • United States