La famille des récepteurs couplés aux protéines G et ses orphelins

G protein-coupled receptors are encoded by one of the mammalian largest gene families. These receptors share a common transmembrane organization, respond to a large variety of structurally different ligands, and regulate intracellular enzymes and channels through heterotrimeric G proteins. The first genes encoding receptors of this family were isolated following the purification of the protein and sequencing of peptides generated by proteolytic cleavage. Subsequently, a number of G protein-coupled receptor genes were cloned through expression screening procedures based either on the binding of a specific ligand, or on the functional coupling of the recombinant receptor to a transduction cascade. Most members in this gene family were however obtained by homology cloning, using cross-hybridization or low-stringency polymerase chain reaction. The result is the availability of more than 140 receptor types and subtypes (olfactory receptors excluded). With a few exceptions, all pharmacologically well-defined receptors have now been cloned. Molecular cloning confirmed the existence of poorly characterized subtypes and uncovered other unsuspected subtypes. Genes encoding uncharacterized receptors have also been made available, either related to identified subfamilies, or defining new subfamilies by themselves. These so-called orphan receptors are waiting for the identification of the corresponding ligands and of their biological function. The availability of cloned human receptors is expected to speed up the search for more specific drugs. Determination of the three dimensional structure of selected recombinant receptors, and computer modelling of receptor-ligand interaction and ligand-mediated receptor activation will probably allow in the long run die rational design of specific agonists and antagonists. The increasing number of reported orphan receptors will certainly be instrumental in the discovery of new regulatory pathways linking cells, with the potential of opening new avenues in pharmacology.