Dual positive and negative regulation of GPCR signaling by GTP hydrolysis

Cell Signal. 2009 Jul;21(7):1151-60. doi: 10.1016/j.cellsig.2009.03.004. Epub 2009 Mar 12.

Abstract

G protein-coupled receptors (GPCRs) regulate a variety of intracellular pathways through their ability to promote the binding of GTP to heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins increases the intrinsic GTPase activity of Galpha-subunits and are widely regarded as negative regulators of G protein signaling. Using yeast we demonstrate that GTP hydrolysis is not only required for desensitization, but is essential for achieving a high maximal (saturated level) response. Thus RGS-mediated GTP hydrolysis acts as both a negative (low stimulation) and positive (high stimulation) regulator of signaling. To account for this we generated a new kinetic model of the G protein cycle where Galpha(GTP) enters an inactive GTP-bound state following effector activation. Furthermore, in vivo and in silico experimentation demonstrates that maximum signaling output first increases and then decreases with RGS concentration. This unimodal, non-monotone dependence on RGS concentration is novel. Analysis of the kinetic model has revealed a dynamic network motif that shows precisely how inclusion of the inactive GTP-bound state for the Galpha produces this unimodal relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • GTP-Binding Protein alpha Subunits / metabolism
  • Gene Deletion
  • Guanosine Triphosphate / metabolism*
  • Hydrolysis
  • Models, Biological
  • Pheromones / metabolism
  • RGS Proteins / metabolism
  • Receptors, G-Protein-Coupled / metabolism*
  • Schizosaccharomyces / metabolism*
  • Schizosaccharomyces pombe Proteins / metabolism
  • Signal Transduction*
  • Time Factors

Substances

  • GTP-Binding Protein alpha Subunits
  • Pheromones
  • RGS Proteins
  • Receptors, G-Protein-Coupled
  • Rgs1 protein, S pombe
  • Schizosaccharomyces pombe Proteins
  • Guanosine Triphosphate