Skeletal muscle RyR1. RyR1 forms a homotetrameric protein complex that is situated in the SR membrane and functions as a Ca²⁺ release channel. The cytosolic part, the “foot,” bridges the gap between the transverse tubular system and the SR. It contains binding sites for various activating ligands, like Ca²⁺ (μM), ATP (nM), calmodulin (nM), caffeine (mM), and ryanodine (nM), and inactivating ligands, like dantrolene (>10 μM), Ca²⁺ (>10 μM), ryanodine (>100 μM), and Mg²⁺ (μM). The transmembrane segments, M3–M10, are numbered according to both the earlier model of Zorzato et al. (108) and the recently modified model of MacLennan and colleagues (109). The first 2 cylinders, with dashed lines, indicate the tentative nature of the composition of the first predicted helical hairpin loop (M3–M4 or M4a–M4b). The long M7 sequence is designated as M7a and M7b. The proposed selectivity filter between M8 and M10 is designated as M9 even though it is clearly not a transmembrane sequence. Mutations causing susceptibility to MH and/or central core disease are indicated. Susceptibility to MH was defined by use of the in vitro contracture test or, in a single case, by the Japanese Ca-induced Ca release test (CICR test). MH/CC, MH with some central cores; CCD, central core disease; CCD/rods, CCD with nemaline rods.