Sex and sugar in yeast: two distinct GPCR systems

Abstract

Although eukaryotic G-protein coupled receptor (GPCR) systems are well known for their ability to detect and mediate rapid responses to extracellular signals, the full range of stimuli to which they respond may not yet have been identified. Activation of GPCRs by hormones, pheromones, odorants, neurotransmitters, light and different taste compounds is well established. However, the recent discovery of a glucose-sensing GPCR system in Saccharomyces cerevisiae has unexpectedly added common nutrients to this list of stimuli. This GPCR system mediates glucose activation of adenylate cyclase during the switch from respirative/gluconeogenic metabolism to fermentation. The GPCR system involved in pheromone signalling in S. cerevisiae has already served as an important model and tool for the study of GPCR systems in higher eukaryotic cell types. Here, we highlight the similarities and differences between these two signalling systems. We also indicate how the new glucose-sensing system can serve as a model for GPCR function and as a tool with which to screen for heterologous components of signalling pathways as well as for novel ligands in high-throughput assays.

Fig. 1. Overview of pheromone and glucose signalling in S. cerevisiae. The putative glucose receptor Gpr1 activates the Gα protein Gpa2, for which no β or γ subunits have been identified yet. Rgs2 stimulates the GTPase activity of Gpa2 and thus inhibits glucose-induced cAMP signalling. Gpa2 is thought to activate adenylate cyclase (Cdc35/Cyr1) but direct biochemical evidence for this is still lacking. The basal activity of adenylate cyclase also depends on the Ras1 and Ras2 proteins of which the signalling function, if any, remains unclear. Activation of PKA by cAMP results in stimulation of growth and pseudohyphal differentiation, loss of stress resistance, mobilization of trehalose and glycogen and in reduced life-span. Pheromone sensing depends on the Ste2 and Ste3 receptors that respectively bind α- and a-factor and that transmit the signal to the heterotrimeric G-protein consisting of the Gα protein Gpa1 and the βγ subunit Ste4 and Ste18. The RGS protein Sst2 is able to diminish signalling by stimulating the GTPase activity of Gpa1. Ste4 recruits both the scaffolding protein Ste5 and Ste20 (which can also be stimulated by Cdc42) to the membrane resulting in activation of the mating MAP kinase cascade (Ste11, Ste7 and Fus3). Activation of the MAP kinase pathway results in growth arrest and conjugation.

Fig. 2. (A) Alignment of putative glucose-sensing G-protein coupled receptors: S. cerevisiae Gpr1, C. albicans Gpr1 and S pombe git3. Transmembrane regions (TM1–7) are indicated in red, residues identical for at least two aligned sequences are in white letters on a dark blue background, residues similar in at least two sequences are shaded in light blue. (B) Alignment of human Gi1 and Gs1, and S. cerevisiae Gpa1 and Gpa2. Identity between Gpa1 and Gi1 is 37%, between Gpa1 and Gs1 29%; identity between Gpa2 and Gi1 is 44% compared to 34% between Gpa2 and Gs1. Residues identical in at least three aligned sequences are in white letters on a dark blue background and similar residues in at least three sequences are shaded in light blue.

Mathias Versele, Katleen Lemaire & Johan M. Thevelein