“…RyR1 R163C is one of the most studied MH mutations in heterologous (HEK293) and homologous expression systems (dyspedic myotubes) as well as in heterozygous knockin mice. Results obtained from single channel recordings, [ 3 H] ryanodine binding and Ca 2+ imaging indicate enhanced basal activity, increased sensitivity to Ca 2+ activation, increased sensitivity to pharmacological activators, and elevated resting cytosolic Ca 2+ concentration (Tong et al, 1997;Avila and Dirksen, 2001;Yang et al, 2003;Yang et al, 2006;Feng et al, 2011;Chen et al, 2018;Iyer et al, 2020). Here, we used chemical cross-linking to demonstrate that R163C impairs RyR1 NTD tetramerization (Figure 1).…”