The movements of Ca2+ within cells in response to external stimuli are complex. Internal Ca2+ release activated by inositol 1,4,5-trisphosphate (InsP3) is now widely established. However, the mechanism of InsP3-induced Ca2+ release, the identity and control of the InsP3-sensitive Ca2+ pool and its relationship to other internal and external Ca2+ pools all remain uncertain. We have characterized a highly sensitive and specific guanine nucleotide-regulatory mechanism that induces rapid and profound movements of intracellular Ca2+ via a mechanism distinct from that activated by InsP3. Using permeabilized neural or smooth muscle cells, application of submicromolar concentrations of GTP induces rapid release of Ca2+ from a compartment that contains within it the InsP3-releasable Ca2+ pool. Although of similar GTP-sensitivity as G-protein-activated events, the apparent dependence on GTP hydrolysis and blockade by GTP gamma S suggest a mechanism distinct from those mediated by known G-proteins. Recent experiments in the presence of oxalate reveal rapid and profound GTP-activated uptake of Ca2+ via a mechanism with identical nucleotide sensitivity and specificity to GTP-induced Ca2+ release. These results were interpreted to suggest that GTP induces a transmembrane conveyance of Ca2+ between different compartments distinguished by oxalate permeability; GTP-induced release probably occurs via a similar mechanism except involving transfer between closed compartments and nonclosed membranes (perhaps the plasma membrane). Recently, it has been revealed that GTP activates a translocation of Ca2+ into the Ca2+ pool from which InsP3 induces release. This is an important observation suggesting that the GTP-activated Ca2+ translocation process may control entry into and hence the size of the InsP3-releasable Ca2+ pool. Indeed, it is possible that GTP-induced Ca2+ release observed in permeabilized cells reflects a reversal of the pathway that functions in intact cells to permit external Ca2+ entry into the InsP3-releasable pool. This type of process could mediate the longer-term secretory or excitatory responses to external receptors which are known to be dependent on external Ca2+.

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