MOLECULAR-GENETICS OF OLFACTORY RECEPTORS

The understanding of the molecular mechanisms underlying olfactory per ception has made considerable progress over the recent pars. Key prote ins involved in the olfactory signal transduction have been cloned, in cluding the GTP-binding protein G(olf), the olfactory-specific type II I adenylyl cyclase, and the nucleotide-gated olfactory ion channel. Th e gene family encoding olfactory receptors was further cloned, by low stringency polymerase chain reaction, from rat, human, dog, mouse and catfish, on the basis of their structural similarities with other G pr otein-coupled receptors. The genes encoding olfactory receptors repres ent a huge family with up to a thousand members expected in mammalian species and up to a hundred in cat-fish. The olfactory receptors exhib it all landmarks of G-protein coupled receptors, including the seven p utative transmembrane segments, and structural characteristics make th em constitute a well identified subfamily. Olfactory receptors display an unusual variability in the sequence of transmembrane segments that are generally conserved between receptor subtypes, suggesting a posit ive selection for mutations occuring in the ligand binding domains. Fo r one of the cloned receptor, the olfactory nature was proven by funct ional expression of the recombinant protein in a baculovirus system, a nd stimulation of the IP3 intracellular cascade. All receptors cloned to date have a putative glycosylation site in the N-terminal extracell ular domain, and potential phosphorylation sites for protein kinase C, cAMP-dependent protein kinase and beta ARK related kinases, that are believed to mediate the functional regulation of receptor function by homologous and heterologous desensitization. As a rule, olfactory rece ptors genes are expressed solely in olfactory mucosa neurons, although some members of this gene family are expressed mainly in testis, with little or no expression in olfactory mucosa. The potential relation o f this finding with sperm chemoattraction remains to be elucidated. Th e genes encoding olfactory receptors seem to be grouped as a limited n umber of clusters in the human genome. Two of these clusters were iden tified on chromosomes 17 and 19.