'Quantal' Ca²⁺ release at the cytoplasmic aspect of the Ins(1,4,5)P₃R channel in smooth muscle

Smooth muscle responds to activation of the inositol (1,4,5)-trisphosphate receptor [Ins(1,4,5)P₃R] with a graded concentration-dependent ('quantal') Ca²⁺ release from the sarcoplasmic reticulum (SR) store. Graded release seems incompatible both with the finite capacity of the store and the Ca²⁺-induced Ca²⁺ release (CICR)-like facility, at Ins(1,4,5)P₃Rs, that, once activated, should release the entire content of SR Ca²⁺. The structural organization of the SR and the regulation of Ins(1,4,5)P₃R activity by inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] and Ca²⁺ have each been proposed to explain 'quantal' Ca²⁺ release. Here, we propose that regulation of Ins(1,4,5)P₃R activity by lumenal Ca²⁺ acting at the cytoplasmic aspect of the receptor might explain 'quantal' Ca²⁺ release in smooth muscle. The entire SR store was found to be lumenally continuous and Ca²⁺ could diffuse freely throughout: peculiarities of SR structure are unlikely to account for 'quantal' release. While Ca²⁺ release was regulated by [Ca²⁺] within the SR, the velocity of release increased (accelerated) during the release process. The extent of acceleration of release determined the peak cytoplasmic [Ca²⁺] and was attenuated by a reduction in SR [Ca²⁺] or an increase in cytoplasmic Ca²⁺ buffering. Positive feedback by released Ca²⁺ acting at the cytoplasmic aspect of Ins(1,4,5)P₃Rs (i.e. CICR-like) might (a) account for the acceleration, (b) provide the regulation of release by SR [Ca²⁺] and (c) explain the 'quantal' release process itself. During Ca²⁺ release, SR [Ca²⁺] and thus unitary Ins(1,4,5)P₃R currents decline, CICR reduces and stops. With increasing [Ins(1,4,5)P₃], coincidental activation of several neighbouring Ins(1,4,5)P₃Rs offsets the reduced Ins(1,4,5)P₃R current to renew CICR and Ca²⁺ release.