Dexras1 inhibits adenylyl cyclase.
Dexras1 is a steroid hormone-induced Ras family G protein that acts as a receptor-independent activator of signaling by Gi/o family heterotrimeric G proteins. We examined the effects of Dexras1 on the activity of adenylyl cylase, a target of inhibitory regulation by Gialpha x GTP. Constitutively active Gsalpha (Q227L) increased cAMP levels 43-fold above baseline, and Dexras1 expression inhibited cAMP levels by 61% (P < 0.01). Dexras1 mediated inhibition of adenylyl cyclase was blocked by treatment pertussis toxin or by co-expression of RGS4, but was not inhibited by with dominant-interfering (G203T or G204A) mutants of Gi alpha2. Dexras1 decreased forskolin-stimulated CREB activation (P < 0.01) and this activity was also inhibited by co-expression of RGS4. These findings indicate that Dexras1 expression leads to ligand-independent activation of both Gialpha- and G(beta)gamma-dependent arms of the Gi signaling cascade, and suggest that Dexras1 may exert physiologically relevant inhibitory effects on the cAMP-PKA-CREB.
Graham
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New Mexico Veterans Affairs Health Care System, Medical Service (111), Departments of Medicine and Biochemistry/Molecular Biology, University of New Mexico School of Medicine, 1501 San Pedro Blvd. SE, Albuquerque, NM 87108, USA.
Qiao
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Dorin
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D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D009154:Mutation; D037342:Pertussis Toxin / Q000494:pharmacology; D015290:Second Messenger Systems; D018631:ras Proteins / Q000502:physiology*
D000067956:Adenylyl Cyclase Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; C400132:RASD1 protein, human; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D018631:ras Proteins; D000262:Adenylyl Cyclases