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

Abstract

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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.