Ca2+ release induced by inositol 1,4,5-trisphosphate is a steady-state phenomenon controlled by luminal Ca2+ in permeabilized cells

Abstract

Low concentrations of inositol 1,4,5-trisphosphate (InsP3) evoke a very rapid mobilization of intracellular Ca2+ stores in many cell types, which can be followed by a further, much slower efflux. Two explanations have been suggested for this biphasic release. The first proposes that the Ca2+ stores vary in their sensitivity to InsP3, and each store releases either its entire contents or nothing (all-or-none release); the second proposes instead that the stores are uniformly sensitive to the effects of InsP3, but that they can release only a fraction of their Ca2+ before their sensitivity is somehow attenuated (steady-state release). Experiments using purified InsP3 receptor molecules reconstituted into lipid vesicles have shown heterogeneity of the receptors in their response to InsP3 under conditions in which the total Ca2+ level at both sides of the receptor is held constant. We now report that in permeabilized A7r5 smooth-muscle cells incubated in Ca(2+)-free medium, the amount of 45Ca2+ remaining in the stores after the rapid transient phase of release is independent of their initial Ca2+ levels, indicating that partially depleted stores are less sensitive to InsP3. Moreover, if the stores are reloaded with 40Ca2+ after the first stimulus, reapplication of the same low concentration of InsP3 will release further 45Ca2+. This recovery of InsP3 sensitivity is almost complete. Under these conditions, Ca2+ release must thus occur by a steady-state mechanism, in which the decreasing Ca2+ content of the stores slows down further release.

‘Quantal’ Ca2+ release reassessed – a clue to oscillation and synchronization

“…Alternatively, the efflux of Ca 2+ may be compensated for by reuptake of Ca 2+ after a rapid release of Ca 2+ , as the activity of store Ca 2+ pumps is accelerated by a decrease in the concentration of Ca 2+ in the lumen of the Ca 2+ store [10]. However, this explanation was also unlikely because the transient Ca 2+ release occurs in the absence of Ca 2+ reuptake [3,4,8,9,[11][12][13].…”

“…Since this model was proposed, a lot of studies have demonstrated that a reduction in the luminal Ca 2+ concentration attenuates Ca 2+ efflux [8,9,[11][12][13]. Koizumi et al [23] have shown that the Ca 2+ release from ryanodine-sensitive stores is also regulated by the luminal Ca 2+ concentration.…”

“…Alternatively, the efflux of Ca 2+ may be compensated for by reuptake of Ca 2+ after a rapid release of Ca 2+ , as the activity of store Ca 2+ pumps is accelerated by a decrease in the concentration of Ca 2+ in the lumen of the Ca 2+ store [10]. However, this explanation was also unlikely because the transient Ca 2+ release occurs in the absence of Ca 2+ reuptake [3,4,8,9,[11][12][13].Another feature of 'quantal' Ca 2+ release is that the amount of Ca 2+ released depends on the dose of agonist or InsP 3 [1,3,4,6,8,9], or caffeine for ryanodine-sensitive Ca 2+ stores [14,15]. Meyer and Stryer [3] suggested that such dose dependent Ca 2+ release acts as an 'increment detector' in response to stepwise increases in stimulus intensity.…”

Endothelin-Induced Sarcoplasmic Reticulum Calcium Depletion Waves in Vascular Smooth Muscle Cells

“…These data collectively suggest that the elevated [Ca 2+ ] SR at the origin and at the rim of the wave plays a crucial role in wave initiation and propagation, and underscores the importance of the previous reports demonstrating that [Ca 2+ ] SR plays a stimulatory role in IP 3 R-mediated Ca 2+ release [26][27][28]. In fact, several reports make strong cases for the existence of a luminal excitatory Ca 2+ binding site on IP 3 R, which would provide a straightforward explanation for the stimulating effects of [Ca 2+ ] SR [29][30][31][32].…”

Calcium Mobilization via Intracellular Ion Channels, Store Organization and Mitochondria in Smooth Muscle

“…Rather, at any given [IP 3 ] the entire Ca 2+ store is activated and releases a fraction of its content, becoming partially depleted. Partial depletion may deactivate Ca 2+ release [64,65]. Raising the [IP 3 ] reactivates IP 3 R to renew the Ca 2+ release process.…”