Dexras1 blocks receptor-mediated heterologous sensitization of adenylyl cyclase 1

Biochem Biophys Res Commun. 2005 Jul 8;332(3):913-20. doi: 10.1016/j.bbrc.2005.05.041.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / genetics
  • Adenylyl Cyclases / metabolism*
  • Binding Sites / genetics
  • Calcimycin / pharmacology
  • Cell Line
  • Cyclic AMP / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / metabolism
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism
  • GTP-Binding Proteins / pharmacology*
  • Humans
  • Kinetics
  • Mutagenesis, Site-Directed
  • Quinpirole / pharmacology
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Transfection
  • ras Proteins / genetics
  • ras Proteins / metabolism
  • ras Proteins / pharmacology*

Substances

  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • RASD1 protein, human
  • Receptors, Dopamine D2
  • Recombinant Proteins
  • dopamine D2L receptor
  • Quinpirole
  • Calcimycin
  • Cyclic AMP
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Proteins
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • ras Proteins
  • Adenylyl Cyclases