Dexras1 blocks receptor-mediated heterologous sensitization of adenylyl cyclase 1

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 Gβγ-dependent as demonstrated using the C-terminus of β-adrenergic receptor kinase (βARK-ct). These data suggest that Dexras1 selectively regulates receptor-mediated Gβγ signaling pathways.