RyR3 amplifies RyR1-mediated Ca2+-induced Ca2+ release in neonatal mammalian skeletal muscle

The neonatal mammalian skeletal muscle contains both type 1 and type 3 ryan odine receptors (RyR1 and RyR3) located in the sarcoplasmic reticulum membr ane. An allosteric interaction between RyR1 and dihydropyridine receptors l ocated in the plasma membrane mediates voltage-induced Ca2+ release (VICR) from the sarcoplasmic reticulum. RyR3, which disappears in adult muscle, is not involved in VICR, and the role of the transiently expressed RyR3 remai ns elusive. Here we demonstrate that RyR1 participates in both VICR an Ca2-induced Ca2+ release (CICR) and that RyR3 amplifies RyR1-mediated CICR in neonatal skeletal muscle. Confocal measurements of intracellular Ca2+ in pr imary cultured mouse skeletal myotubes reveal active sites of Ca2+ release caused by peripheral coupling between dihydropyridine receptors and RyR1. I n myotubes lacking RyR3, the peripheral VICR component is unaffected, and R yR1s alone are able to support inward CICR propagation in most cells at an average speed of similar to 190 mum/s. With the co-presence of RyR1 and RyR 3 in wild-type cells, unmitigated radial CICR propagates at 2,440 mum/s. Be cause neonatal skeletal muscle lacks a well developed transverse tubule sys tem, the RyM reinforcement of CICR seems to ensure a robust, uniform, and s ynchronous activation of Ca2+ release throughout the cell body. Such functi onal interplay between RyR1 and RyR3 can serve important roles in Ca2+ sign aling of cell differentiation and muscle contraction.