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 or 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 D2L receptor-mediated activation of ERK 1/2 by approximately 50%,. Heterologous sensitization of AC1 induced by persistent activation of D2L 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 G beta gamma-dependent as demonstrated using the C-terminus of P-adrenergic receptor kinase (beta ARK-ct). These data suggest that Dexras1 selectively regulates receptor-mediated G beta gamma signaling pathways. (c) 2005 Elsevier Inc. All rights reserved.