Regulation of the inositol 1,4,5-trisphosphate-activated Ca2+ channel by activation of G proteins.
Streptolysin O-permeable pancreatic acini were used to study the regulation of the inositol 1,4,5-trisphosphate (IP3)-activated Ca2+ channel (IPACC) by agonists and antagonists. Measurements of the apparent affinity for IP3 (KappIP3) showed that the IPACC is dynamically controlled during cell stimulation and inhibition, i.e. agonists decreased and antagonists increased KappIP3. KappIP3 was also independently regulated by thimerosal, Ca2+ content of the stores, the incubation temperature, activation of protein kinases, and inhibition of protein phosphatases, but none of these mechanisms contributed to the regulation by agonists and antagonists. Incubating the cells with low concentration of GTPgammaS or AIF3 reproduced the effect of the agonist on KappIP3. Moreover, low [GTPgammaS] allowed activation of the IPACC by agonists at basal levels of IP3 and markedly impaired channel inactivation by antagonists. Channel sensitization by GTPgammaS also restored the ability of thimerosal to mobilize Ca2+ from internal stores with no change in cellular IP3 levels. The combination of low [GTPgammaS] and thimerosal locked the channel in an open, antagonist-insensitive state. All modulatory effects of GTPgammaS are independent of phospholipase C activation and IP3 production. We propose that the dynamic regulation of the IPACC by a G protein-dependent mechanism can play a major role in triggering and maintaining Ca2+ oscillations at low agonist concentrations when minimal or no changes in IP3 level take place.
Xu
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X
Department of Physiology, University of Texas Southwestern Medical School, Dallas 75235, USA.
Zeng
W
W
Muallem
S
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology*; D051381:Rats; D013849:Thimerosal / Q000494:pharmacology
D015220:Calcium Channels; D013849:Thimerosal; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015544:Inositol 1,4,5-Trisphosphate; D019204:GTP-Binding Proteins; D002118:Calcium