Cardiac muscle contractility is controlled by myoplasmic calcium (Ca) concentration. Sarcoplasmic reticulum plays an essential role in the regulation of [Ca]. Depolarization of the sarcolemma induces Ca release from the sarcoplasmic reticulum, leading to the muscle contraction. On the other hand, Ca uptake by the sarcoplasmic reticulum into the lumen results in the muscle relaxation. The Ca release from the sarcoplasmic reticulum is mediated by Ca release channel. Using ryanodine as a molecular probe, the calcium release channel has been isolated, purified and characterized. Morphological studies have confirmed its identity with the feet structure which spans between the transverse tubule and the junctional face of the sarcoplasmic reticulum. The cardiac Ca release channel cDNA encodes 4969 amino acids with a molecular weight of 564,711. The analysis of the sequence indicates that 10 potential transmembrane sequences in the COOH-terminal fifth of the molecule and two additional nearer to the center of the molecule could contribute to the formation of the Ca conducting pore. The remainder of the molecule is hydrophilic and constitutes the cytoplasmic domain which corresponds to the feet structure. Northern blot analysis has shown that the cardiac Ca release channel is expressed in heart and brain. The channel is modulated by Ca, ATP, calmodulin, and phosphorylation. A potential modulator binding domain has been identified in the molecule by searching consensus sequences and investigation of a causal mutation for malignant hyperthermia, the primary defect of which exists in the skeletal Ca release channel.(ABSTRACT TRUNCATED AT 250 WORDS)