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

Abstract

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.

Caffeine and 2-Aminoethoxydiphenyl Borate (2-APB) Have Different Ability to Inhibit Intracellular Calcium Mobilization in Pancreatic Acinar Cell

“…CCh-induced initial Ca 2＋ mobilization has been recognized as a result of Ca 2＋ release from internal stores, because those are essentially unaffected by removal of extracellular Ca 2＋ , and those are not observed by store depletion using thapsigargin or cyclopiazonic acid (CPA), SERCA inhibitors [3]. We found that caffeine blocked lower CCh- ]i rise is blocked by RyR antagonist [8,29]. Caffeine increases both the open time and open probability of RyR in a cooperative manner with both Ca 2＋ and ATP, and therefore enhances the affinity of RyR for the physiological activator [30].…”

Implications of α v β 3 Integrin Signaling in the Regulation of Ca 2+ Waves and Myogenic Tone in Cerebral Arteries

“…Findings in Figure 3 showed that RGD but not the control RAD peptide lowered MLC 20 phosphorylation in pressurized cerebral arteries. It also showed that in RGDtreated arteries, the subsequent application of diltiazem but not ryanodine (an SR-depleting agent) further reduced MLC 20 phosphorylation. This finding is consistent with α v β 3 integrin driving this key phosphorylation step through Ca 2+ wave suppression rather than through substantive changes in L-type Ca 2+ channel activity.…”

“…Exposing RGD-treated arteries to diltiazem further reduced pressure-induced MLC 20 phosphorylation, whereas ryanodine application had no effect. The latter observation is consistent with α v β 3 integrin signaling directing the phosphorylation of this key contractile protein through Ca 2+ wave generation.…”

“…These discrete asynchronous Ca 2+ events facilitate MLC 20 phosphorylation and, in part, myogenic tone by influencing both MLC kinase and MLC phosphatase activity. 18,20,21 In this study of the cerebral circulation, we investigated whether the α V β 3 integrin facilitates Ca 2+ wave generation and myogenic tone through a signaling cascade, involving PLCγ1 and IP 3 R. To test this hypothesis, we used a methodological approach that synergistically combined pressure myography, rapid Ca 2+ imaging, and Western blot analysis. We found that inhibiting α V β 3 integrin partially impaired myogenic tone, demonstrating the modest role of SR Ca 2+ waves in the generation of myogenic tone.…”

Ca2+ oscillations mediated by exogenous GTP in Paramecium cells: assessment of possible Ca2+ sources

“…A feedback between Ca 2+ mobilisation and Ca 2+ -activated and Ca 2+ -inhibited processes can cause [Ca 2+ ] i oscillations in widely different cells [62][63][64][65][66][67][68][69]. This could encompass, e.g., phospholipase C and Ca 2+ -inhibited Ca 2+ release via InsP 3 receptors.…”