Oligomerization of G-protein-coupled receptors: lessons from the yeast Saccharomyces cerevisiae.

G-protein-coupled receptors (GPCR) signaling is an evolutionarily ancient mechanism used by all eukaryotes to sense environmental stimuli and mediate cell-cell communication (7, 28). During evolution, GPCR genes expanded enormously in number and diversity. Whereas only three of the ∼5,900 genes in the yeast Saccharomyces cerevisiae encode GPCRs, at least 55 of the ∼12,000 genes in Dictyostelium encode GPCRs (19), and more than 1,000 of the ∼22,000 genes in humans encode receptors of this class (28). GPCRs are of crucial physiologic importance. In eukaryotic microorganisms, GPCRs regulate cell growth, development, morphogenesis, motility, and life span. In humans they mediate the action of hundreds of peptide hormones, sensory stimuli, autacoids, neurotransmitters, and chemokines. GPCRs also are targets of many clinically important drugs as well as drugs of abuse. Despite exhibiting striking diversity in primary sequence and biologic function, GPCRs possess the same fundamental architecture, consisting of seven transmembrane (TM) domains and share common mechanisms of signal transduction (85). GPCRs transduce extracellular signals by coupling to heterotrimeric guanine nucleotide binding proteins (G proteins) consisting of α, β, and γ subunits. Activated GPCRs stimulate exchange of GTP for GDP on Gα subunits, dissociating Gα and Gβγ subunits that, in turn, trigger biological responses by binding effector proteins that regulate second messenger production, protein kinase cascades, cytoskeletal organization, gene transcription, and ion channel activity. GPCRs also signal by G protein-independent mechanisms through recruitment of scaffold proteins such as β-arrestins (reviewed in reference 54). In the budding yeast S. cerevisiae, GPCR signaling regulates two biologic processes: conjugation and nutrient sensing (reviewed in references 15 and 106). During conjugation, a mating type cells secrete a-factor, a 12-residue farnesylated oligopeptide pheromone that binds the G-protein-coupled a-factor receptor (STE3 gene product) expressed only by cells of the α mating type. Conversely, α cells secrete α-factor, an unmodified 13-residue peptide pheromone that binds the G-protein-coupled α-factor receptor (STE2 gene product) expressed only by cells of the a mating type. Although a- and α-factor receptors are unrelated in primary sequence, they trigger similar intracellular responses by activating the same G protein-linked mitogen-activated protein kinase cascade. Many fundamentally important aspects of GPCR signaling were first elucidated in budding yeast (reviewed in reference 16), including cloning of the first nonsensory GPCR, signaling by Gβγ subunits, GPCR ubiquitination during endocytosis, signaling via mitogen-activated protein kinase cascades and scaffolding proteins, and G protein regulation by RGS proteins. The third GPCR in budding yeast, encoded by the GPR1 gene, is a likely receptor for glucose, sucrose, and possibly other ligands (55). This receptor regulates yeast pseudohyphal differentiation, cell size, and life span (44, 58, 102, 109). The Gpr1 homolog of the pathogenic fungus Candida albicans promotes the yeast-to-hyphae transition (67). Gpr1 in S. cerevisiae signals via a pathway using a classical Gα subunit homolog (113) and novel kelch-repeat proteins (3, 35, 36) but lacking typical Gβγ subunits. Like budding yeast, the fission yeast Schizosaccharomyces pombe possesses three GPCRs (reviewed in reference 41). The mam2+ and mam3+ genes encode receptors for the peptide mating pheromones p-factor and m-factor, respectively, whereas the git3+ gene encodes a putative glucose receptor. In this review we highlight current understanding of GPCR oligomerization revealed by studies of the α-factor receptor of budding yeast. With the exception of Mam2 in fission yeast, GPCR oligomerization in other eukaryotic microorganisms has yet to be investigated.