Comparative Ultrastructure of Ca2+ Release Units in Skeletal and Cardiac Muscle

The sarcoplasmic reticulum (SR) of striated muscle fibers interacts with exterior membranes (surface membrane and transverse tubules) to form junctions that are involved in the internal release of calcium during excitation-contraction coupling. Release of calcium through the ryanodine receptors (RyRs) or calcium release channels of the SR is under the control of the L type calcium channels or dihydropyridine receptors (DHPRs) of exterior membranes. Interacting clusters of the two proteins constitute calcium release units. The cytoplasmic domains of RyRs are visible as large electron-dense structures (the feet) with four identical subunits in the junctional gap separating SR from exterior membranes. In freeze-fracture replicas of skeletal muscle, large intramembrane particles are grouped into clusters of tetrads in the exterior membranes, and the tetrads are located in correspondence of the four subunits of the feet. Lack of tetrads in dysgenic muscle fibers with a null mutation for DHPRs and appearance of the tetrads after transfection with cDNA for DHPR indicate identity of tetrads with four DHPRs. In cardiac muscle, DHPRs are located at the sites of SR-surface junctions, but they are not grouped into tetrads. This is consistent with a possible direct DHPR-RyR interaction in skeletal but not in cardiac muscle. The size and distribution of SR-surface junctions in skeletal and cardiac muscles provide further clues to their function.