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Cardiovascular Research 2001 51(1):80-88; doi:10.1016/S0008-6363(01)00273-5
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

PKA-dependent phosphorylation of cardiac myosin binding protein C in transgenic mice

Qinglin Yang1, Timothy E. Hewett, Raisa Klevitsky, Atsushi Sanbe, Xuejun Wang and Jeffrey Robbins*

Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Children's Hospital Research Foundation, 333 Burnet Avenue, Cincinnati, OH 45229-3039, USA

* Corresponding author. Tel.: +1-513-636-8098; fax: +1-513-636-3852 jeff.robbins{at}chmcc.org

Objective: To investigate the physiological role of cAMP-dependent protein kinase A (PKA)-mediated, cardiac myosin binding protein C (MyBP-C) phosphorylation. Methods: A cardiac MyBP-C cDNA lacking nine amino acids, which contained a phosphorylation site, was made, and subsequently used to generate multiple lines of transgenic mice. Upon confirming that a partial replacement of endogenous protein with transgenic protein occurred, the biochemical and physiological consequences were studied. PKA-dependent phosphorylation assays were used to estimate the phosphorylation states of major cardiac PKA substrates. Myofibril Mg-ATPase activities were also measured. Isolated working heart and whole animal exercise studies were used to measure the physiological changes. Results: Transgenic mice displayed a compensatory response, with PKA-mediated phosphorylation of both troponin I and phospholamban showing significant increases. The remaining endogenous cardiac MyBP-C also showed increased phosphorylation levels. Maximal Mg2+-ATPase activity was increased. Significant functional changes at both the whole organ and whole animal levels also occurred. Parameters reflecting cardiac contractility and relaxation increased about 22 and 25%, respectively, in the mutant relative to wild type mice (n=5, P<0.001). In young adults the capacity for stress exercise, quantitated using an exercise treadmill regimen, was substantially enhanced (n=6, P<0.01). Conclusions: Cardiac MyBP-C phosphorylation plays an important physiological role and that the protein's degree of phosphorylation is coordinated with the phosphorylation levels of other proteins within the contractile apparatus.

KEYWORDS Contractile apparatus; Contractile function; Histo(patholo)logy; Gene expression; Signal transduction; Protein phosphorylation

1 Present address: Cardiovascular Research Institute, Morehouse School of Medicine, Westview Dr. SW, Atlanta, GA 30310, USA.


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