Role of calmodulin methionine residues in mediating productive association with cardiac ryanodine receptors

Edward M. Balog, Laura E. Norton, David D. Thomas, Bradley R. Fruen

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Calmodulin (CaM) binds to the cardiac ryanodine receptor Ca2+ release channel (RyR2) with high affinity and may act as a regulatory channel subunit. Here we determine the role of CaM Met residues in the productive association of CaM with RyR2, as assessed via determinations of [ 3H]ryanodine and [35S]CaM binding to cardiac muscle sarcoplasmic reticulum (SR) vesicles. Oxidation of all nine CaM Met residues abolished the productive association of CaM with RyR2. Substitution of the COOH-terminal Mets of CaM with Leu decreased the extent of CaM inhibition of cardiac SR (CSR) vesicle [3H]ryanodine binding. In contrast, replacing the NH2-terminal Met of CaM with Leu increased the concentration of CaM required to inhibit CSR [3H]ryanodine binding but did not alter the extent of inhibition. Site-specific substitution of individual CaM Met residues with Gln demonstrated that Met124 was required for both high-affinity CaM binding to RyR2 and for maximal CaM inhibition. These results thus identify a Met residue critical for the productive association of CaM with RyR2 channels.

Original languageEnglish (US)
Pages (from-to)H794-H799
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume290
Issue number2
DOIs
StatePublished - Feb 2006

Keywords

  • Excitation-contraction
  • Methionine sulfoxide
  • Oxidative stress
  • Ryanodine receptor Ca release channel
  • Sarcoplasmic reticulum

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