Differential effects of regulator of G protein signaling (RGS) proteins on serotonin 5-HT1A, 5-HT2A, and dopamine D2 receptor-mediated signaling and adenylyl cyclase activity

Cell Signal. 2004 Jun;16(6):711-21. doi: 10.1016/j.cellsig.2003.11.006.


Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) for Galpha subunits, attenuating G-protein-coupled receptor signal transduction. The present study tested the ability of members of different subfamilies of RGS proteins to modulate both G-protein-dependent and -independent signaling in mammalian cells. RGS4, RGS10, and RGSZ1 significantly attenuated Galphai-mediated signaling by 5-HT1A, but not by dopamine D2, receptor-expressing cells. Additionally, RGS4 and RGS10 significantly inhibited forskolin-stimulated cAMP production in both cell lines. In contrast, RGS2, RGS7, and RGSZ1 had no effect on forskolin-stimulated cAMP production in these cells. RGS2 and RGS7 significantly decreased Galphaq-mediated signaling by 5-HT2A receptors, confirming that the RGS4 and RGS10 effects on forskolin-stimulated cAMP production were specific, and not simply due to overexpression. Interestingly, similar expression levels of RGS4 protein resulted in greater inhibition of G-protein-independent cAMP production compared to G-protein-dependent GAP activity. Our results suggest specificity and selectivity of RGS proteins on G-protein-dependent and -independent signaling in mammalian cells.

MeSH terms

  • Adenylyl Cyclases / drug effects
  • Animals
  • Colforsin / pharmacology
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Enzyme Activation / drug effects
  • GTP-Binding Proteins / metabolism*
  • RGS Proteins / metabolism*
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Serotonin, 5-HT1 / metabolism*
  • Receptors, Serotonin, 5-HT2 / metabolism*
  • Signal Transduction / physiology


  • RGS Proteins
  • Receptors, Dopamine D2
  • Receptors, Serotonin, 5-HT1
  • Receptors, Serotonin, 5-HT2
  • RGS4 protein
  • Colforsin
  • Cyclic AMP
  • GTP-Binding Proteins
  • Adenylyl Cyclases