Origin and mechanisms of Ca2+ waves in smooth muscle as revealed by localized photolysis of caged inositol 1,4,5-trisphosphate

The cytosolic Ca2+ concentration ([Ca2+](c)) controls diverse cellular events via various Ca2+ signaling patterns; the latter are influenced by the method of cell activation. Here, in single-voltage clamped smooth muscle cells, sarcolemma depolarization generated uniform increases in [Ca2+](c) throughout the cell entirely by Ca2+ influx. On the other hand, the Ca2+ signal produced by InsP(3)-generating agonists was a propagated wave. Using localized uncaged InsP(3), the forward movement of the Ca2+ wave arose from Ca2+-induced Ca2+ release at the InsP(3) receptor (InsP(3)R) without ryanodine receptor involvement. The decline in [Ca2+](c) ( the back of the wave) occurred from a functional compartmentalization of the store, which rendered the site of InsP(3)-mediated Ca2+ release, and only this site, refractory to the phosphoinositide. The functional compartmentalization arose by a localized feedback deactivation of InsP(3) receptors produced by an increased [Ca2+](c) rather than a reduced luminal [Ca2+] or an increased cytoplasmic [InsP(3)]. The deactivation of the InsP(3) receptor was delayed in onset, compared with the time of the rise in [Ca2+](c), persisted (>30 s) even when [Ca2+](c) had regained resting levels, and was not prevented by kinase or phosphatase inhibitors. Thus different forms of cell activation generate distinct Ca2+ signaling patterns in smooth muscle. Sarcolemma Ca2+ entry increases [Ca2+](c) uniformly; agonists activate InsP(3)R and produce Ca2+ waves. Waves progress by Ca2+-induced Ca2+ release at InsP(3)R, and persistent Ca2+-dependent inhibition of InsP(3)R accounts for the decline in [Ca2+](c) at the back of the wave.