Key result
Oxidation of all nine calmodulin methionine residues abolished its productive association with cardiac ryanodine receptors, with Met124 identified as critical for high-affinity binding and inhibition.
Met124 is a critical residue for the productive association and inhibitory function of calmodulin on cardiac ryanodine receptors.
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Oxidative calmodulin modification may disrupt RyR regulation in stressed myocardium; hypothesis-generating for arrhythmia pathways, requires in vivo confirmation.
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.
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Balog et al. (2005) studied this question. Oxidation or substitution of Calmodulin Methionine residues vs. Unmodified Calmodulin was evaluated on Productive association of CaM with RyR2 (assessed via [3H]ryanodine and [35S]CaM binding). Oxidation of all nine calmodulin methionine residues abolished its productive association with cardiac ryanodine receptors, with Met124 identified as critical for high-affinity binding and inhibition.
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