Published online before print February 27, 2003, doi: 10.1161/01.RES.0000064566.91495.0C
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on August 27, 2002
Revised on February 11, 2003
Accepted on February 20, 2003
Calmodulin Regulation of Excitation-Contraction Coupling in Cardiac Myocytes
Dongmei Yang ;
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.
* To whom correspondence should be addressed. 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
This article has been cited by other articles:
 |
|
 |
|
  D. Yang, W.-Z. Zhu, B. Xiao, D. X.P. Brochet, S.R. W. Chen, E. G. Lakatta, R.-P. Xiao, and H. Cheng Ca2+/Calmodulin Kinase II-Dependent Phosphorylation of Ryanodine Receptors Suppresses Ca2+ Sparks and Ca2+ Waves in Cardiac Myocytes Circ. Res., February 16, 2007; 100(3): 399 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xiong, Q. K. Kleerekoper, R. He, J. A. Putkey, and S. L. Hamilton Sites on Calmodulin That Interact with the C-terminal Tail of Cav1.2 Channel J. Biol. Chem., February 25, 2005; 280(8): 7070 - 7079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. H.T. Wehrens, S. E. Lehnart, S. R. Reiken, and A. R. Marks Ca2+/Calmodulin-Dependent Protein Kinase II Phosphorylation Regulates the Cardiac Ryanodine Receptor Circ. Res., April 2, 2004; 94(6): e61 - e70. [Abstract] [Full Text] [PDF]
|
|