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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenylyl Cyclases / genetics
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Adenylyl Cyclases / metabolism*
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Binding Sites / genetics
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Calcimycin / pharmacology
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Cell Line
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Cyclic AMP / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
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GTP-Binding Protein beta Subunits / metabolism
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GTP-Binding Protein gamma Subunits / metabolism
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism
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GTP-Binding Proteins / pharmacology*
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Humans
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Kinetics
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Mutagenesis, Site-Directed
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Quinpirole / pharmacology
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Receptors, Dopamine D2 / genetics
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Receptors, Dopamine D2 / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction
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Transfection
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ras Proteins / genetics
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ras Proteins / metabolism
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ras Proteins / pharmacology*
Substances
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G-protein Beta gamma
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GTP-Binding Protein beta Subunits
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GTP-Binding Protein gamma Subunits
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RASD1 protein, human
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Receptors, Dopamine D2
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Recombinant Proteins
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dopamine D2L receptor
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Quinpirole
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Calcimycin
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Cyclic AMP
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Extracellular Signal-Regulated MAP Kinases
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GTP-Binding Proteins
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GTP-Binding Protein alpha Subunits, Gi-Go
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ras Proteins
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Adenylyl Cyclases