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Phosphorylation and regulation of the Ca2+-pumping ATPase in cardiac sarcoplasmic reticulum by calcium/calmodulin-dependent protein kinase

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Abstract

In cardiac muscle, a membrane-associated Ca2+/calmodulin-dependent protein kinase (CaM kinase) phosphorylates the Ca2+-pumping ATPase in addition to its previously characterized substrates, phospholamban and Ca2+-release channel (ryanodine receptor). The phosphorylated amino acid in the Ca2+-ATPase has been identified as serine. Posphorylation of the Ca2+-ATPase is rapid and is reversible by a membrane-associated protein phosphatase. Ca2+-ATPase purified from cardiac SR underwent phosphorylation by exogenous CaM kinase, and the phosphorylated enzyme displayed twofold greater catalytic activity without alteration in its Ca2+-sensitivity. The phosphorylation of the Ca2+-ATPase was found to be isoform-specific in that the cardiac and slow-twitch skeletal muscle isoform (SERCA 2), but not the fast-twitch skeletal muscle isoform (SERCA 1), underwent phosphorylation by CaM kinase. Studies using SERCA 1 and SERCA 2 isoforms and their mutants expressed in a heterelogous cell system have resulted in i) confirmation of the isoform specificity of Ca2+-ATPase phosphorylation by CaM kinase, ii) identification of Ser38 as the site in SERCA 2 phosphorylated by CaM kinase, and iii) demonstration of phosphorylation-induced increase in Vmax of Ca2+ transport by the SERCA 2 enzyme. These observations suggest that in cardiac and slow-twitch skeletal muscle direct phosphorylation of the SR Ca2+-ATPase by the membrane-bound CaM kinase may serve to stimulate Ca2+ sequestration and therefore, the speed of muscle relaxation.

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  1. Department of Physiology, University of Western Ontario, Medical Sciences Building, N6A 5C1, London, Ontario, Canada

    N. Naraynan & A. Xu

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  1. N. Naraynan
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Naraynan, N., Xu, A. Phosphorylation and regulation of the Ca2+-pumping ATPase in cardiac sarcoplasmic reticulum by calcium/calmodulin-dependent protein kinase. Basic Res Cardiol 92 (Suppl 1), 25–35 (1997). https://doi.org/10.1007/BF00794065

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