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(Circulation Research. 2003;92:659.)
© 2003 American Heart Association, Inc.

Cellular Biology

Calmodulin Regulation of Excitation-Contraction Coupling in Cardiac Myocytes

Dongmei Yang, Long-Sheng Song, Wei-Zhong Zhu, Khalid Chakir, Wei Wang, Caihong Wu, Yibin Wang, Rui-Ping Xiao, S.R. Wayne Chen, Heping Cheng

From the National Laboratory of Biomembrane and Membrane Biotechnology (D.Y., C.W., H.C.), College of Life Sciences, Peking University, Beijing, China; Laboratory of Cardiovascular Sciences (D.Y., L.-S.S., W.-Z.Z., K.C., W.W., R.-P.X., H.C.), National Institute on Aging, National Institutes of Health, Baltimore, Md; the Department of Physiology (Y.W.), School of Medicine, University of Maryland, Baltimore, Md; Cardiovascular Research Group (S.R.W.C.), Departments of Physiology & Biophysics and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.

Correspondence to Heping Cheng, PhD, Laboratory of Cardiovascular Sciences, NIA, NIH, Baltimore, MD 21224.E-mail chengp{at}grc.nia.nih.gov

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.

Key Words: calmodulin • Ca²⁺/calmodulin-dependent protein kinase II • L-type Ca²⁺ channels • phospholamban

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