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RGS protein specificity towards Gq- and Gi/o-mediated ERK 1/2 and Akt activation, in vitro

Thomas Anger1, Nils Klintworth, Christian Stumpf

  • 1Department for Cardiology, Friedrich-Alexander University Erlangen, 91054 Erlangen, German. th_anger@arcor.de

Journal of Biochemistry and Molecular Biology
|December 1, 2007
PubMed

Insights

Cardiac RGS proteins show specific modulation of G(q) and G(i/o) signaling pathways, impacting Extracellular Regulated Kinases (ERK) and Protein Kinase B (Akt) phosphorylation. This specificity suggests complex counter-regulatory mechanisms beyond direct G protein interaction.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Cardiovascular research

Background:

  • Extracellular Regulated Kinases (ERK) and Protein Kinase B (Akt) are key intracellular targets for growth factor signaling.
  • G protein-coupled receptors (GPCRs) activate ERK and Akt pathways via G(q) and G(i/o) proteins.
  • Regulator of G protein Signaling (RGS) proteins modulate GPCR signaling.

Purpose of the Study:

  • To investigate the specific roles of cardiac RGS proteins in modulating G(q) and G(i/o)-induced ERK and Akt phosphorylation.
  • To understand the specificity of RGS protein interactions within the muscarinic receptor signaling network.

Main Methods:

  • Utilized COS-7 cells expressing specific muscarinic receptors (M(2) or M(3)) to isolate G(q) and G(i/o) signaling.
  • Employed Western blot analysis to quantify changes in ERK and Akt phosphorylation.
  • Performed co-expression studies with various RGS proteins to assess their modulatory effects.

Main Results:

  • Carbachol stimulation increased ERK and Akt phosphorylation in M(2)/M(3) expressing cells.
  • RGS3s/RGS3 specifically blunted M(3)/G(q)-induced Akt activation, while RGS2/RGS5 also inhibited ERK activation.
  • All tested RGS proteins inhibited M(2)/G(i/o)-induced Akt activation; RGS2 had no effect on M(2)/G(i/o)-induced ERK activation.

Conclusions:

  • Cardiac RGS proteins exhibit distinct specificity in regulating G(q) and G(i/o)-mediated ERK and Akt activation.
  • The observed specificity is not solely due to RGS protein selectivity for G(q) or G(i/o) proteins.
  • Complex counter-regulatory mechanisms and signaling crosstalk likely influence GPCR-induced ERK and Akt activation sensitivity to RGS protein regulation.

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