Published online before print December 22, 2005, doi: 10.1161/01.RES.0000200739.90811.9f
© 2006 American Heart Association, Inc.
Cellular Biology |
Increased Sarcoplasmic Reticulum Calcium Leak but Unaltered Contractility by Acute CaMKII Overexpression in Isolated Rabbit Cardiac Myocytes
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.
Correspondence to Lars S. Maier, MD, Abt. Kardiologie & Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. E-mail lmaier{at}med.uni-goettingen.de
The predominant cardiac Ca2+/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 Ca2+ current (ICa) was increased by 31% (–7.1±0.5 versus –5.4±0.5 pA/pF, P<0.05). Ca2+ transient amplitude was not significantly reduced (–27%, P=0.22), despite dramatically reduced sarcoplasmic reticulum (SR) Ca2+ content (41%; P<0.05). Thus fractional SR Ca2+ release was increased by 60% (P<0.05). Diastolic SR Ca2+ leak assessed by Ca2+ spark frequency (normalized to SR Ca2+ 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 Ca2+ leak may explain reduced SR Ca2+ content, despite measured levels of SR Ca2+-ATPase and Na+/Ca2+ 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 Ca2+ leak and reduced SR Ca2+ content but without reducing twitch contraction and Ca2+ transients. We conclude that this is attributable to concomitant enhancement of fractional SR Ca2+ release in CaMKIIC myocytes (ie, CaMKII-dependent enhancement of RyR Ca2+ sensitivity during diastole and systole) and increased ICa.
Key Words: calcium • CaMKII • excitation–contraction coupling • sarcoplasmic reticulum
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