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Modulation of Agonist-Induced Inositol Phosphate Metabolism by Cyclic Adenosine 3',5'- Monophosphate in Adrenal Glomerulosa Cells

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland 20892

Address requests for reprints to: Dr. K. J. Catt, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room B1L-400, 9000 Rockville Pike, Bethesda, Maryland 20892.

Abstract

Activation of the cAMP messenger system was found to cause specific changes in angiotensin-II (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 [Ins(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 Ins(1,4,5)P₃ was inhibited, consistent with increased activity of phospholipase-C. Continued exposure to 8Br-cAMP for 5–16 h caused selective enhancement of the All-induced increases in D-myo-inositol 1,3,4,6-tetra-kisphosphate [Ins(1,3,4,6)P₄] and myo-inositol 1,4,5,6-tetrakisphosphate. The long term effect of 8Br-cAMP on the 6-phosphorylated InsP₄ isomers, but not the initial enhancement of Ins(1,4,5)P₃ formation, was inhibited by cycloheximide. The characteristic biphasic kinetics of All-induced Ins(1,4,5)P₃ formation were also changed by prolonged treatment with 8Br-cAMP to a monophasic response in which Ins(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-trisphosphate [Ins(1,3,4)P₃] to Ins(1,3,4,6)P₄ was consistently increased, whereas dephosphorylation of Ins(1,4,5)P₃ to D-myo-inositol 1,4-bisphosphate and of D-myo-inositol 1,3,4,5-tetrakisphosphate to Ins(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 Ins(1,3,4)P₃ to lns(1,3,4,6)P₄, as well as decreased Ins(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.

FOOTNOTES

^* Permanent address: Department of Physiology, Semmelweis University School of Medicine, P.O. Box 259, H-1444 Budapest, Hungary.

Received for publication June 28, 1990. Revision received July 30, 1990. Accepted for publication July 31, 1990.

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