"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