MODULATION OF AGONIST-INDUCED INOSITOL PHOSPHATE-METABOLISM BY CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE IN ADRENAL GLOMERULOSA CELLS

Activation of the cAMP messenger system was found to cause specific changes in angiotensin-ll (All)-induced inositol phosphate production and metabolism in bovine adrenal glomerulosa cells. Pretreatment of [3H]inositol-labeled glomerulosa cells with 8-bromo-cAMP (8Br-cAMP) caused both short and long term changes in the inositol phosphate response to stimulation by All. Exposure to 8Br-cAMP initially caused dose-dependent enhancement (ED50 = 0.7 μm) of the stimulatory action of All (50 nm; 10 min) on the formation of D-myo-inositol 1,4,5-trisphosphate [lns(1,4,5)P3] and its immediate metabolites. This effect of 8Br-cAMP was also observed in permeabilized [3H]inositol-labeled glomerulosa cells in which degradation of lns(1,4,5)P3 was inhibited, consistent with increased activity of phos-pholipase-C. Continued exposure to 8Br-cAMP for 5-16 h caused selective enhancement of the Allinduced increases in D-myo-inositol 1,3,4,6-tetra-kisphosphate [lns(1,3,4,6)P4] and myo-inositol 1,4,5,6-tetrakisphosphate. The long term effect of 8Br-cAMP on the 6-phosphorylated lnsP4 isomers, but not the initial enhancement of lns(1,4,5)P3 formation, was inhibited by cycloheximide. The characteristic biphasic kinetics of All-induced lns(1,4,5)P3 formation were also changed by prolonged treatment with 8Br-cAMP to a monophasic response in which lns(1,4,5)P3 increased rapidly and remained elevated during All stimulation. In permeabilized glomerulosa cells treated with 8Br-cAMP for 16 h, the conversion of D-myo-inositol 1,3,4-trisphos-phate [lns(1,3,4)P3] to lns(1,3,4,6)P4 was consistently increased, whereas dephosphorylation of lns(1,4,5)P3 to D-myo-inositol 1,4-bisphosphate and of D-myo-inositol 1,3,4,5-tetrakisphosphate to lns(1,3,4)P3, was reduced. Thus, the increased production of higher inositol phosphates during All stimulation of 8Br-cAMP-treated cells results in part from increased phosphorylation of lns(1,3,4)P3 to lns(1,3,4,6)P4, as well as decreased lns(1,4,5)P3-5-phosphatase activity. These findings demonstrate that interactions between the cAMP and inositol phosphate signal generation pathways in the glomerulosa cell lead to enhanced production of higher inositol phosphates that could mediate long term changes in the function of agonist-stimulated adrenal cells. © 1990 by The Endocrine Society.