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• W2165620104 abstract "The predominant cardiac Ca 2+ /calmodulin-dependent protein kinase (CaMK) is CaMKIIδ. Here we acutely overexpress CaMKIIδ C using adenovirus-mediated gene transfer in adult rabbit ventricular myocytes. This circumvents confounding adaptive effects in CaMKIIδ C transgenic mice. CaMKIIδ C protein expression and activation state (autophosphorylation) were increased 5- to 6-fold. Basal twitch contraction amplitude and kinetics (1 Hz) were not changed in CaMKIIδ C versus LacZ expressing myocytes. However, the contraction–frequency relationship was more negative, frequency-dependent acceleration of relaxation was enhanced (τ 0.5Hz /τ 3Hz =2.14±0.10 versus 1.87±0.10), and peak Ca 2+ current ( I Ca ) was increased by 31% (−7.1±0.5 versus −5.4±0.5 pA/pF, P <0.05). Ca 2+ transient amplitude was not significantly reduced (−27%, P =0.22), despite dramatically reduced sarcoplasmic reticulum (SR) Ca 2+ content (41%; P <0.05). Thus fractional SR Ca 2+ release was increased by 60% ( P <0.05). Diastolic SR Ca 2+ leak assessed by Ca 2+ spark frequency (normalized to SR Ca 2+ load) was increased by 88% in CaMKIIδ C 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 2+ leak may explain reduced SR Ca 2+ content, despite measured levels of SR Ca 2+ -ATPase and Na + /Ca 2+ exchange expression and function being unaltered. Ryanodine receptor (RyR) phosphorylation in CaMKIIδ C myocytes was increased at both Ser2809 and Ser2815, but FKBP12.6 coimmunoprecipitation with RyR was unaltered. This shows for the first time that acute CaMKIIδ C overexpression alters RyR function, leading to enhanced SR Ca 2+ leak and reduced SR Ca 2+ content but without reducing twitch contraction and Ca 2+ transients. We conclude that this is attributable to concomitant enhancement of fractional SR Ca 2+ release in CaMKIIδ C myocytes (ie, CaMKII-dependent enhancement of RyR Ca 2+ sensitivity during diastole and systole) and increased I Ca ." @default.
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• W2165620104 date "2006-02-03" @default.
• W2165620104 modified "2023-09-27" @default.
• W2165620104 title "Increased Sarcoplasmic Reticulum Calcium Leak but Unaltered Contractility by Acute CaMKII Overexpression in Isolated Rabbit Cardiac Myocytes" @default.
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• W2165620104 doi "https://doi.org/10.1161/01.res.0000200739.90811.9f" @default.
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