Published online before print December 22, 2005, doi: 10.1161/01.RES.0000200739.90811.9f
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Submitted on July 18, 2005
Revised on October 31, 2005
Accepted on December 8, 2005
Increased Sarcoplasmic Reticulum Calcium Leak but Unaltered Contractility by Acute CaMKII Overexpression in Isolated Rabbit Cardiac Myocytes
Michael Kohlhaas ;
From the Abteilung Kardiologie & Pneumologie/Herzzentrum (M.K., T.S., D.Z., N.D., A.S., S.W., L.S.M.), Georg-August-Universität Göttingen, Germany; Department of Pharmacology (T.Z., J.H.B.), University of California San Diego; and Department of Physiology (L.C., D.M.B.), Stritch School of Medicine, Loyola University Chicago, Ill.
* To whom correspondence should be addressed. E-mail: lmaier{at}med.uni-goettingen.de.
The predominant cardiac Ca/calmodulin-dependent protein kinase (CaMK) is CaMKII
. Here we acutely overexpress CaMKIIC using adenovirus-mediated gene transfer in adult rabbit ventricular myocytes. This circumvents confounding adaptive effects in CaMKIIC transgenic mice. CaMKIIC protein expression and activation state (autophosphorylation) were increased 5- to 6-fold. Basal twitch contraction amplitude and kinetics (1 Hz) were not changed in CaMKIIC versus LacZ expressing myocytes. However, the contraction-frequency relationship was more negative, frequency-dependent acceleration of relaxation was enhanced (
0.5Hz/3Hz=2.14±0.10 versus 1.87±0.10), and peak Ca current (ICa) was increased by 31% (-7.1±0.5 versus -5.4±0.5 pA/pF, P<0.05). Ca transient amplitude was not significantly reduced (-27%, P=0.22), despite dramatically reduced sarcoplasmic reticulum (SR) Ca content (41%; P<0.05). Thus fractional SR Ca release was increased by 60% (P<0.05). Diastolic SR Ca leak assessed by Ca spark frequency (normalized to SR Ca load) was increased by 88% in CaMKIIC versus LacZ myocytes (P<0.05; in an multiplicity-of-infection-dependent manner), an effect blocked by CaMKII inhibitors KN-93 and autocamtide-2-related inhibitory peptide. This enhanced SR Ca leak may explain reduced SR Ca content, despite measured levels of SR Ca-ATPase and Na/Ca exchange expression and function being unaltered. Ryanodine receptor (RyR) phosphorylation in CaMKIIC myocytes was increased at both Ser2809 and Ser2815, but FKBP12.6 coimmunoprecipitation with RyR was unaltered. This shows for the first time that acute CaMKIIC overexpression alters RyR function, leading to enhanced SR Ca leak and reduced SR Ca content but without reducing twitch contraction and Ca transients. We conclude that this is attributable to concomitant enhancement of fractional SR Ca release in CaMKIIC myocytes (ie, CaMKII-dependent enhancement of RyR Ca sensitivity during diastole and systole) and increased ICa.
Key words: calcium • CaMKII • excitation-contraction coupling • sarcoplasmic reticulum
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