title: Dexras1 blocks receptor-mediated heterologous sensitization of adenylyl cyclase 1.
abstract: Dexras1/AGS1/RasD1 is a member of the Ras superfamily of monomeric G proteins and has been suggested to disrupt receptor-G protein signaling. We examined the ability of Dexras1 to modulate dopamine D(2L) receptor regulation of adenylyl cyclase (AC) type 1 in HEK293 cells. Acute D(2L) receptor-mediated inhibition of A23187-stimulated AC1 activity (IC50, 4.0+/-1.4 nM; 50+/-3% inhibition) was not altered in the presence of Dexras1 (IC50, 2.4+/-1.3 nM, 50+/-1% inhibition); however, Dexras1 blocked acute D(2L) receptor-mediated activation of ERK 1/2 by approximately 50%. Heterologous sensitization of AC1 induced by persistent activation of D(2L) receptors was completely blocked by Dexras1 under basal and A23187-stimulated conditions. The block of sensitization was concentration-dependent and was not observed with a nucleotide binding-deficient Dexras1G31V mutant. Sensitization of AC1 was Gbetagamma-dependent as demonstrated using the C-terminus of beta-adrenergic receptor kinase (betaARK-ct). These data suggest that Dexras1 selectively regulates receptor-mediated Gbetagamma signaling pathways.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47909, USA.
authors.forename: Chau H
authors.initials: CH
authors.lastname: Nguyen
authors.forename: Val J
authors.initials: VJ
authors.lastname: Watts
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C400132:RASD1 protein, human; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; C113776:dopamine D2L receptor; D019257:Quinpirole; D000001:Calcimycin; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D018631:ras Proteins; D000262:Adenylyl Cyclases