Fig. 8. Smooth muscle quantal Ca²⁺ release. Ins(1,4,5)P₃-evoked Ca²⁺ release is exquisitely sensitive to the SR Ca²⁺ content and the development of positive feedback. With low agonist [Ins(1,4,5)P₃] and a replete SR (top left-hand panel), Ins(1,4,5)P₃-mediated Ca²⁺ release from an activated (purple) Ins(1,4,5)P₃R (IP₃R) induces a release of Ca²⁺ from the SR, resulting in a reduction in SR lumenal [Ca²⁺] (blue low, red high). This release produces a large rise in [Ca²⁺]_c (red colour) that overlaps neighbouring quiescent (yellow) Ins(1,4,5)P₃Rs. The rise in [Ca²⁺]_c then stimulates adjacent Ins(1,4,5)P₃Rs and a CICR-like process there (top right-hand panel). During release, the SR Ca²⁺ content declines and with it the unitary Ins(1,4,5)P₃R Ca²⁺ current. As a result, the local [Ca²⁺] rise at the cytoplasmic aspect of Ins(1,4,5)P₃Rs is reduced (top right-hand panel). The extent of activation of neighbouring Ins(1,4,5)P₃Rs through CICR declines and eventually ceases – even in the continued presence of the agonist. With increasing concentrations of agonist (lower panel), the probability of coincidental activation of two or more neighbouring Ins(1,4,5)P₃Rs increases. While activation of single receptors cannot generate substantial CICR, the local [Ca²⁺] near neighbouring Ins(1,4,5)P₃Rs as a result of two receptors being activated is again sufficient to generate CICR and the positive feedback results in significant Ca²⁺ release. Thus, the extent of Ca²⁺ release is determined by the positive-feedback facility. The declining unitary currents, as a result of Ca²⁺ release, are offset by an increased number of Ins(1,4,5)P₃Rs being activated simultaneously to generate CICR and renew the release process.