Much recent progress has been made in our understanding of the mechanism of sarcoplasmic reticulum Ca2+ release in skeletal muscle. Vertebrate skeletal muscle excitation-contraction (E-C) coupling is thought to occur by a “mechanical coupling”� mechanism involving protein-protein interactions that lead to activation of the sarcoplasmic reticulum (SR) ryanodine receptor (RyR)/Ca2+ release channel by the voltage-sensing transverse (T−) tubule dihydropyridine receptor (DHPR)/Ca2+ channel. In a subsequent step, the released Ca2+ amplify SR Ca2+ release by activating release channels that are not linked to the DHPR. Experiments with mutant muscle cells have indicated that skeletal muscle specific DHPR and RyR isoforms are required for skeletal muscle E-C coupling. A direct functional and structural interaction between a DHPR-derived peptide and the RyR has been described. The interaction between the DHPR and RyR may be stabilized by other proteins such as triadin (a SR junctional protein) and modulated by phosphorylation of the DHPR.

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