The evolutionarily triumphant G-protein-coupled receptor.

Among all of the known proteins in the human genome, the G-protein-coupled receptors (GPCRs) may be the most versatile. They know how to manipulate the evolutionary forces that govern diversity by copying one ancestral gene and turning it into thousands of different proteins that can transduce light, smells, taste, nucleotides, lipids, peptides, and various other chemical compounds. They all seemingly do this by the same mechanism but can selectively and intimately interact with specific ligands and effectors. How did they do this? In this issue of Molecular Pharmacology, the tremendous effort of Fredriksson et al. (2003) provides the first overall road map of GPCR ancestry in a single mammalian genome using 342 functional nonolfactory human GPCR sequences. Their results show that there are five main families: Glutamate, Rhodopsin, Adhesion, Frizzled/taste2, and Secretin, forming the GRAFS classification system. From the chromosomal positions of the genes (paralogons) and the finding of “fingerprint” motifs, the authors support the theory that GPCRs in the GRAFS family share a common ancestor and evolved through gene duplication and exon shuffling. Their data also formulated a distinct family of GPCRs called the adhesion family and showed that the two taste receptor groups (TAS1 and TAS2) are not phylogenetically linked. The analysis divided the TAS1 receptors into the glutamate receptor family, whereas the TAS2 receptors grouped with Frizzled. The GPCRs are so diverse and important to our physiology that they are the most pursued as drug targets. They include about 1000 to 2000 members and comprise 1% of the human genome. Even nematodes cannot live without them or may even require them more; more than a thousand GPCRs make up 5% of the nematode genome (Bargmann, 1998). With the cloning of a plant cytokine GPCR, GCR1 from Arabidopsis thaliana, the ancestry of GPCRs is even more ancient and may predate the divergence of plants and animals (Plakidou-Dymock et al., 1998). Although not yet characterized, there is also evidence to suggest that GPCRs exist in protozoa (New and Wong, 1998); certainly, the presence of the cAMP receptors in Dictyostelium discoideum, suggests the presence of cAMP receptors in humans (Bankir et al., 2002). Although not linked to G-proteins, bacteriorhodopsin itself suggests that the ancestor of the GPCR-like structure can even reside in bacteria. The phylogenetic analysis of these proteins may provide the tools to understanding the targets, drug design, and classification of the many unknown orphan receptors.