Location of Repository

Dual positive and negative regulation of GPCR signaling by GTP hydrolysis

By Benjamin Smith, Claire Hill, Emma L. Godfrey, D. A. Rand, Hugo van den Berg, Steven Thornton, Matthew N. Hodgkin, John Davey and Graham Ladds

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 increase the intrinsic GTPase activity of G-subunits and are widely regarded as\ud 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\ud positive (high stimulation) regulator of signaling. To account for this we generated a new kinetic model of the G protein cycle where G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\ud 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 G produces this unimodal relationship.\u

Topics: QR
Publisher: Elsevier Inc.
Year: 2009
OAI identifier: oai:wrap.warwick.ac.uk:485

Suggested articles

Preview

Citations

  1. (1995). Methods in Molecular Genetics, Pheromone procedures in fission yeast, doi
  2. (2008). Trends Endocrinol.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.