Sarcolemma agonist-induced interactions between InsP3 and ryanodine receptors in Ca2+ oscillations and waves in smooth muscle.

Smooth muscle cells respond to InsP(3)-generating (sarcolemma-acting) neurotransmitters and hormones by releasing Ca(2+) from the internal store. However, the release of Ca(2+) does not occur uniformly throughout the cytoplasm but often into a localized area before being transmitted to other regions of the cell in the form of Ca(2+) waves and oscillations to actively spread information within and between cells. Yet, despite their significance, our understanding of the generation of oscillations to waves is incomplete. A major aspect of controversy centres on whether or not Ca(2+) released from the InsP(3) receptor activates RyRs (ryanodine receptors) to generate further release by Ca(2+)-induced Ca(2+) release and propagate waves or whether the entire process arises from InsP(3) receptor activity alone. Under normal physiological conditions the [Ca(2+)] required to activate RyR (approx. 15 microM) exceeds the bulk average [Ca(2+)](c) (cytoplasmic Ca(2+) concentration) generated by InsP(3) receptor activity (<1 microM). Progression of waves and oscillations by RyR activity would require a loss of control of RyR activity and an unrestrained positive feedback on Ca(2+) release. Under store-overload conditions, RyR Ca(2+) sensitivity is increased and this enables waves to be induced by RyR activity. However, the relevance of these Ca(2+)-release events to normal physiological functioning is unclear. The InsP(3) receptor, on the other hand, is activated by Ca(2+) over the physiological range (up to 300 nM) and deactivated by higher [Ca(2+)](c) (>300 nM), features that favour intermittent activity of the receptor as occurs in waves and oscillations. Experimental evidence for the involvement of RyR relies mainly on pharmacological approaches in the intact cell where poor drug specificity could have led to ambiguous results. In this brief review the possible interactions between InsP(3) receptors and RyR in the generation of oscillations and waves will be discussed. Evidence is presented that RyRs are not required for InsP(3)-mediated Ca(2+) transients. Notwithstanding, ryanodine can inhibit InsP(3)-mediated Ca(2+) responses after RyR activity has been induced by caffeine or by steady depolarization which evokes spontaneous transient outward currents (a sarcolemmal manifestation of RyR activity). Ryanodine inhibits InsP(3)-mediated Ca(2+) transients by depleting the store of Ca(2+) rather than by RyR involvement in the InsP(3)-mediated Ca(2+) increase.