Calcium-Induced Calcium Release in Smooth Muscle: Loose Coupling between the Action Potential and Calcium Release

Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary calcium release events (calcium sparks) associated with the opening of L-type Ca²⁺ channels. In heart cells, a tight coupling between the gating of single L-type Ca²⁺ channels and ryanodine receptors (RYRs) underlies calcium release. Here we demonstrate that L-type Ca²⁺ channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca²⁺ sparks and propagated Ca²⁺ waves. However, unlike CICR in cardiac muscle, RYR channel opening is not tightly linked to the gating of L-type Ca²⁺ channels. L-type Ca²⁺ channels can open without triggering Ca²⁺ sparks and triggered Ca²⁺ sparks are often observed after channel closure. CICR is a function of the net flux of Ca²⁺ ions into the cytosol, rather than the single channel amplitude of L-type Ca²⁺ channels. Moreover, unlike CICR in striated muscle, calcium release is completely eliminated by cytosolic calcium buffering. Thus, L-type Ca²⁺ channels are loosely coupled to RYR through an increase in global [Ca²⁺] due to an increase in the effective distance between L-type Ca²⁺ channels and RYR, resulting in an uncoupling of the obligate relationship that exists in striated muscle between the action potential and calcium release.