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

Qinglin Yang, Timothy E. Hewett, Raisa Klevitsky, Atsushi Sanbe, Xuejun Wang, Jeffrey Robbins

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)80-88
Number of pages9
JournalCardiovascular research
Volume51
Issue number1
DOIs
StatePublished - 2001

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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