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Homocysteine effects classical pathway of GPCR down regulation: Galpha(q/11), Galpha(12/13), G(i/o)

T P Vacek1, U Sen, N Tyagi

  • 1Department of Physiology & Biophysics, School of Medicine, University of Louisville, Health Sciences Center, Louisville, KY 40202, USA.

Molecular and Cellular Biochemistry
|September 9, 2008
PubMed

Insights

Homocysteine (Hcy) activates G protein-coupled receptors (GPCRs), initiating their down-regulation. This study reveals Hcy

Area of Science:

  • Cardiovascular Biology
  • Cellular Signaling
  • Molecular Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) regulate cardiac function via intracellular effectors.
  • Pertussis toxin (PTX) suppression of homocysteine (Hcy)-induced ERK phosphorylation suggests GPCR involvement in Hcy signaling.
  • GPCR activation leads to down-regulation involving ERK, GRK2, and beta-arrestin1.

Purpose of the Study:

  • To investigate if Hcy treatment activates and down-regulates GPCRs.
  • To elucidate the specific molecular mechanisms of Hcy-induced GPCR signaling.

Main Methods:

  • Microvascular endothelial cells were treated with Hcy.
  • Western blotting was used to quantify phospho-ERK1, phospho-GRK2, ERK1, GRK2, and beta-actin expression.
  • Changes in beta-arrestin1, Galpha(q/11), Galpha(12/13), and G(i/o) protein levels were assessed.

Main Results:

  • Hcy treatment dephosphorylated GRK2, enhancing its activity.
  • Hcy activated GPCRs, leading to their subsequent down-regulation.
  • Hcy decreased the cellular content of beta-arrestin1, Galpha(q/11), Galpha(12/13), and G(i/o) proteins.

Conclusions:

  • Hcy acts as an agonist, activating GPCRs and initiating their down-regulation.
  • The findings support a novel signaling pathway where Hcy modulates GPCRs, impacting cellular proteins involved in signal transduction.
  • This research provides evidence for Hcy's role in cardiovascular cellular signaling.

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