Variable Dependence of Signaling Output on Agonist Occupancy of Ste2p, a G Protein-coupled Receptor in Yeast

J Biol Chem. 2016 Nov 11;291(46):24261-24279. doi: 10.1074/jbc.M116.733006. Epub 2016 Sep 19.

Abstract

We report here on the relationship between ligand binding and signaling responses in the yeast pheromone response pathway, a well characterized G protein-coupled receptor system. Responses to agonist (α-factor) by cells expressing widely varying numbers of receptors depend primarily on fractional occupancy, not the absolute number of agonist-bound receptors. Furthermore, the concentration of competitive antagonist required to inhibit α-factor-dependent signaling is more than 10-fold higher than predicted based on the known ligand affinities. Thus, responses to a particular number of agonist-bound receptors can vary greatly, depending on whether there are unoccupied or antagonist-bound receptors present on the same cell surface. This behavior does not appear to be due to pre-coupling of receptors to G protein or to the Sst2p regulator of G protein signaling. The results are consistent with a signaling response that is determined by the integration of positive signals from agonist-occupied receptors and inhibitory signals from unoccupied receptors, where the inhibitory signals can be diminished by antagonist binding.

Keywords: G protein; G protein-coupled receptor (GPCR); pheromone; receptor; regulator of G protein signaling (RGS); signal transduction; signaling; yeast.

MeSH terms

  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Receptors, Mating Factor / genetics
  • Receptors, Mating Factor / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction / physiology*

Substances

  • GTPase-Activating Proteins
  • Receptors, Mating Factor
  • SST2 protein, S cerevisiae
  • STE2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins