Type 1 inositol (1,4,5)-trisphosphate receptor activates ryanodine receptor 1 to mediate calcium spark signaling in adult mammalian skeletal muscle

Functional coupling between inositol (1,4,5)-trisphosphate receptor (IP₃R) and ryanodine receptor (RyR) represents a critical component of intracellular Ca²⁺signaling in many excitable cells; however, the role of this mechanism in skeletal muscle remains elusive. In skeletal muscle, RyR-mediated Ca²⁺ sparks are suppressed in resting conditions, whereas application of transient osmotic stress can trigger activation of Ca²⁺ sparks that are restricted to the periphery of the fiber. Here we show that onset of these spatially confined Ca²⁺ sparks involves interaction between activation of IP₃Rand RyR near the sarcolemmal membrane. Pharmacological prevention of IP₃ production or inhibition of IP₃R channel activity abolishes stress-induced Ca²⁺ sparks in skeletal muscle. Although genetic ablation of the type 2 IP ₃R does not appear to affect Ca²⁺ sparks in skeletal muscle, specific silencing of the type 1 IP₃R leads to ablation of stress-induced Ca²⁺ sparks. Our data indicate that membranedelimited signaling involving cross-talk between IP₃R1 and RyR1 contributes to Ca²⁺ spark activation in skeletal muscle.