Effect of Inositol 1,3,4,5-Tetrakisphosphate on Inositol Trisphosphate-activated Ca Signaling in Mouse Lacrimal Acinar Cells

In mouse lacrimal acinar cells, microinjection of the metabolically stable analog of inositol 1,4,5-trisphosphate, inositol 2,4,5-trisphosphate ((2,4,5)IP ), stimulated both intracellular Ca mobilization and Ca entry. Microinjection of inositol 1,3,4,5-tetrakisphosphate ((1,3,4,5)IP ), the inositol 1,4,5-trisphosphate-3-kinase product, was ineffective at mobilizing intracellular Ca or activating Ca entry. In lacrimal cells previously microinjected with submaximal levels of( 2 , 4 , 5 ) IP , the subsequent microinjection of low to moderate concentrations of ( 1 , 3 , 4 , 5 ) IP did not result in additional release of intracellular Ca , nor did it potentiate the Ca entry phase attributable to( 2 , 4 , 5 ) IP . However, as previously demonstrated (Bird, G. S. J., Rossier, M. F., Hughes, A. R., Shears, S. B., Armstrong, D. L., and Putney, J. W., Jr. (1991) Nature 352, 162-165), additional injections of ( 2 , 4 , 5 ) IP induced further mobilization of intracellular Ca and increased the elevated and sustained Ca entry phase. Introduction of high concentrations of ( 1 , 3 , 4 , 5 ) IP appeared to inhibit or block the ( 2 , 4 , 5 ) IP -induced Ca entry phase. These results were consistent with the observed effect of ( 1 , 3 , 4 , 5 ) IP in permeabilized lacrimal cells, where ( 1 , 3 , 4 , 5 ) IP did not release cellular Ca but at high concentrations inhibited the ability of submaximal concentrations of( 2 , 4 , 5 ) IP to release Ca . Likewise, injection of a high concentration of( 1 , 3 , 4 , 5 ) IP prior to injection of ( 2 , 4 , 5 ) IP blocked both release and influx of Ca . The inhibitory action of( 1 , 3 , 4 , 5 ) IP on Ca signaling observed in intact cells occurred at concentrations that might be obtained in agonist-stimulated cells. However, in permeabilized cells,( 1 , 3 , 4 , 5 ) IP inhibited Ca mobilization at concentrations exceeding those likely to occur in agonist-stimulated cells. These results suggest that physiologically relevant levels of( 1 , 3 , 4 , 5 ) IP in the cell cytoplasm do not release Ca , nor do they potentiate inositol trisphosphate-induced Ca entry across the plasma membrane. Rather, the possibility is raised that ( 1 , 3 , 4 , 5 ) IP or one of its metabolites could function as a negative feedback on Ca mobilization by inhibiting inositol 1,4,5-trisphosphate-induced Ca release.