Type 3 ryanodine receptors of skeletal muscle are segregated in a parajunctional position

A key event in skeletal muscle activation is the rapid release of Ca2+ from the sarcoplasmic reticulum (SR), the Ca2+ storage organelle in the muscle cell. The surface membrane/transverse tubules and the SR form functional units (calcium release units containing one or two couplons or junctions), where the voltage-sensing dihydropyridine receptor of the surface membrane interacts with the SR Ca2+ release channel [ryanodine receptor (RyR)] and depolarization of the cell membrane is converted into Ca2+ release from the SR. Although RyR1 is the most important isoform in skeletal muscle, some muscles also express high levels of RyR3, an isoform with a wide tissue distribution. The cytoplasmic domains of RyRs are visible in the electron microscope as periodically disposed feet. We find that, in muscles containing only RyR1, feet are exclusively located over the junctional SR surface facing the surface membrane/transverse tubule. In muscles containing RyR1 as well as RyR3, additional feet are located in lateral parajunctional regions immediately adjacent to junctional SR. Biochemical content of RyR3 and content of parajunctional feet are highly correlated in different muscles and the disposition of parajunctional versus junctional feet are notably different. On the basis of these two observations, we postulate that RyR3s are restricted to the parajunctional region, and thus their activation must be indirect and derivative during excitation- contraction coupling.