Subtype specificity of the ryanodine receptor for Ca2+ signal amplification in excitation‐contraction coupling.

In excitable cells membrane depolarization is translated into intracellular Ca2+ signals. The ryanodine receptor (RyR) amplifies the Ca2+ signal by releasing Ca2+ from the intracellular Ca2+ store upon receipt of a message from the dihydropyridine receptor (DHPR) on the plasma membrane in striated muscle. There are two distinct mechanisms for the amplification of Ca2+ signalling. In cardiac cells depolarization‐dependent Ca2+ influx through DHPR triggers Ca2+‐induced Ca2+ release via RyR, while in skeletal muscle cells a voltage‐induced change in DHPR is thought to be mechanically transmitted, without a requirement for Ca2+ influx, to RyR to cause it to open. In expression experiments using mutant skeletal myocytes lacking an intrinsic subtype of RyR (RyR‐1), we demonstrate that RyR‐1, but not the cardiac subtype (RyR‐2), is capable of supporting skeletal muscle‐type coupling. Furthermore, when RyR‐2 was expressed in skeletal myocytes, we observed depolarization‐independent spontaneous Ca2+ waves and oscillations, which suggests that RyR‐2 is prone to regenerative Ca2+ release responses. These results demonstrate functional diversity among RyR subtypes and indicate that the subtype of RyR is the key to Ca2+ signal amplification.