Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of cultured normal rat kidney cells with virazole or mycophenolic acid which are inhibitors of IMP dehydrogenase decreases by 50 to 70% the ability of prostaglandin E1 or isoproterenol to elevate cAMP levels. Inhibition is maximal by 2 h. The response to cholera toxin is not significantly decreased. Basal cAMP is not affected. Under these conditions, GTP is decreased by 80%, ATP is only 10 to 15% decreased, and UTP and CTP are slightly increased. Normal GTP levels and the responses to prostaglandin E1 and isoproterenol are restored if guanosine, but not inosine, is added with the inhibitor. The response to isoproterenol is recovered within 5 min after removal of mycophenolic acid. Desensitization to prostaglandin E1 or isoproterenol stimulation occurs under conditions where GTP is 80% decreased. These results in intact cells provide direct evidence for a role for GTP in the activation of adenylate cyclase and support previous conclusions from studies with cell homogenates.
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PMID:Evidence in intact cells for an involvement of GTP in the activation of adenylate cyclase. 21 45

Studies from our laboratory in osteoblast-like cells have shown that the increase in EGF receptor expression in response to PTH was cyclic AMP mediated and was blocked by treatment with retinoic acid (RA). The present studies investigate the mechanism for this effect of RA on PTH actions. UMR 106-01 cells were exposed to RA and were tested for cAMP response to PTH as well as for (125)I PTH binding. cAMP production in response to PTH was markedly decreased by RA (25.1 +/- 1.6% of control) whereas there was only a slight decrease in PTH binding in response to RA. For the study of adenylate cyclase activity, membranes were isolated from intact cells that had been exposed to RA. Treatment with RA decreased PTH-stimulated adenylate cyclase activity; however, forskolin-stimulated enzyme activity was unchanged. Treatment of intact cells with pertussis toxin, to inactivate Gi, did not alter the inhibitory effect of RA on PTH-stimulated adenylate cyclase activity. Addition of GppNHp, a non-hydrolyzable analogue of GTP, completely restored the response to PTH in the membranes. Therefore, we examined the activity of IMP dehydrogenase, the rate-limiting enzyme for GTP biosynthesis, and GMP reductase which counteracts the effect of the synthetic enzyme. Treatment with RA for 48 hours increased GMP reductase activity by 240.9 +/- 24.2% and decreased IMP dehydrogenase activity to 67.5 +/- 8.8% of control values. These data indicate that RA impairs the response to PTH in intact cells. This blunted response was preserved in membrane preparations but was corrected by GTP. The RA-induced alterations of enzymes involved in the GTP biosynthetic pathway in a direction that favors a decrease in GTP biosynthesis provide an explanation for the inhibitory effect of RA on PTH actions.
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PMID:Mechanism of retinoic acid induced attenuation of PTH action in UMR 106-01 cells. 1213 38