Key result
Expression of a Ca2+-insensitive CaM mutant, CaM(1-4), in cultured rat ventricular myocytes increased CaMKII activity, augmented L-type Ca2+ current, and elevated SR Ca2+ content.
Expression of a Ca2+-insensitive calmodulin mutant in cardiac myocytes unexpectedly activates CaMKII, demonstrating calmodulin's critical role in modulating calcium dynamics during excitation-contraction coupling.
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May modulate myocyte Ca2+ handling via CaMKII; leaves open in vivo relevance to human arrhythmias.
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.
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Yang et al. (2003) studied Cultured rat ventricular myocytes. Adenoviral expression of mutant CaM(1-4) was evaluated on Amplitude and decay time of Ca2+ transients and contraction, L-type Ca2+ current amplitude, CaMKII activity. Expression of a Ca2+-insensitive CaM mutant, CaM(1-4), in cultured rat ventricular myocytes increased CaMKII activity, augmented L-type Ca2+ current, and elevated SR Ca2+ content.
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