A tryptophan residue in the caffeine-binding site of the ryanodine receptor controls the structure of the Ca2+-binding site to regulate Ca2+ sensitivity.
A specific tryptophan residue in the caffeine-binding site of ryanodine receptors regulates Ca2+ sensitivity, explaining the mechanism of channel activation and certain arrhythmogenic mutations.
Abstract Ryanodine receptors (RyRs) are Ca 2+ release channels in the sarcoplasmic reticulum of skeletal and cardiac muscles and are essential for muscle contraction. Mutations in genes encoding RyRs cause various muscle and arrhythmogenic heart diseases. Although RyR channels are activated by Ca 2+ , the actual mechanism of Ca 2+ binding remains largely unknown. Here, we report the molecular basis of Ca 2+ binding to RyRs for channel activation and discuss its implications in disease states. RyR1 and RyR2 carrying mutations in putative Ca 2+ and caffeine-binding sites were functionally analysed. The results were interpreted with respect to recent near-atomic resolution RyR1 structures in various ligand states. We demonstrate that a tryptophan residue in the caffeine-binding site controls the structure of the Ca 2+ -binding site to regulate the Ca 2+ sensitivity. Our results reveal the initial step of RyR channel activation by Ca 2+ and explain the molecular mechanism of Ca 2+ sensitization by caffeine and disease-causing mutations.
Murayama et al. (Tue,) conducted a other in Arrhythmogenic heart diseases (CPVT) / Ryanodine receptor function. Mutagenesis of RyR caffeine-binding site and caffeine application vs. Wild-type RyR / Control solution was evaluated on Ca2+ sensitivity (pCa50) and [3H]ryanodine binding. A tryptophan residue in the caffeine-binding site of the ryanodine receptor controls the structure of the Ca2+-binding site to regulate Ca2+ sensitivity.
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