CHAPTER 24 – Human Olfactory Receptors

Olfaction, the sense of smell, is a versatile and sensitive mechanism for detecting volatile odorous molecules. It is mediated by hundreds of olfactory receptor (OR) proteins in the membrane of the chemosensory neurons, extended by the formation of long cilia. Odorant binding initiates a cascade of signal transduction events that involve a G-proteindependent elevation of cAMP second messenger and opening of cAMP-gated ion channels. The olfactory system utilizes a combinatorial receptor-coding scheme to discriminate different odorants. In humans, a repertoire of more than 1000 OR genes has been elucidated by cloning and genomic data mining. Genes of this "olfactory subgenome", the largest subgroup within the G-protein-coupled receptor (GPCR) hyperfamily, are disposed in dozens of clusters on most human chromosomes. This genomic disposition is accounted for by an elaborate process of gene and cluster duplication, as well as gene conversion events. Approximately two-thirds of all human ORs are pseudogenes that have accumulated up to 27 frame-disrupting mutations. Such an observation is consistent with the diminished importance of the sense of smell in primates, including humans. The OR subgenome consists of 17 gene families, which belong to either class I (fish-like) or class II (tetrapod-specific) receptors. Interestingly, the proportion of intact genes is greater among class I receptors, suggesting they have greater functional importance. Future studies should involve a considerable augmentation of ligand-receptor relationships in the olfactory system in mammals. This should include improved protein expression methodologies, as well as genetic studies that would link olfactory sensitivity phenotypes to OR genotypes.