Olfactory receptors expressed in the cell membranes of olfactory receptor neurons are responsible for the detection of odor molecules. Activated olfactory receptors are the initial player in a signal transduction cascade which ultimately produces a nerve impulse which is transmitted to the brain. These receptors are members of the class A rhodopsin-like family of G protein-coupled receptors (GPCRs).[1][2] The olfactory receptors form a multigene family consisting of over 900 genes in humans and 1500 genes in mice.[3]
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In vertebrates, the olfactory receptors are located in the cilia of the olfactory sensory neurons.[4] In insects, olfactory receptors are located on the antennae and other chemosensory organs.[5] Sperm cells also express odor receptors, which are thought to be involved in chemotaxis to find the egg cell.[6]
Rather than binding specific ligands like most receptors, olfactory receptors display affinity for a range of odor molecules, and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities.[7] Once the odorant has bound to the odor receptor, the receptor undergoes structural changes and it binds and activates the olfactory-type G protein on the inside of the olfactory receptor neuron. The G protein (Golf and/or Gs)[8] in turn activates the lyase - adenylate cyclase - which converts ATP into cyclic AMP (cAMP). The cAMP opens cyclic nucleotide-gated ion channels which allow calcium and sodium ions to enter into the cell, depolarizing the olfactory receptor neuron and beginning an action potential which carries the information to the brain.
The primary sequences of thousands of olfactory receptors (ORs) are known from the genomes of more than a dozen organisms: they are seven-helix transmembrane proteins, but there are (as of July 2011) no known structures of any OR. There is a highly conserved sequence in roughly three quarters of all ORs that is a tripodal metal ion binding site [9], and Suslick has proposed that the ORs are in fact metalloproteins (mostly likely with zinc, copper and possibly manganese ions) that serve as a Lewis Acid site for binding of many odorant molecules.
In a recent but highly controversial interpretation, it has also been speculated that olfactory receptors might really sense various vibrational energy-levels of a molecule rather than structural motifs via quantum coherence mechanisms.[10] As evidence it has been shown that flies can differentiate between two odor molecules which only differ in hydrogen isotope (which will drastically change vibrational energy levels of the molecule).[11]. Not only could the flies distinguish between the deuterated and non-deuterated forms of an odorant, they could generalise the property of "deuteratedness" to other novel molecules. In addition, they generalised the learned avoidance behaviour to molecules which were not deuterated but did share a significant vibration stretch with the deuterated molecules, a fact which the differential physics of deuteration (below) has difficulty in accounting for.
It should be noted, however, that deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0C for H20 vs. 101.42 for D20; melting points: 0.0C for H20, 3.82C for D2O), pKa (i.e., dissociation constant: 9.71x10^-15 for H20 vs. 1.95x10^-15 for D2O, cf. Heavy_water) and the strength of hydrogen bonding. Such isotope effects are exceedingly common, and so it is well known that deuterium substitution will indeed change the binding constants of molecules to protein receptors.[12]
There are a large number of different odor receptors, with as many as 1,000 in the mammalian genome which represents approximately 3% of the genes in the genome. However not all of these potential odor receptor genes are expressed and are functional. According to an analysis of data derived from the human genome project, humans have approximately 400 functional genes coding for olfactory receptors and the remaining 600 candidates are pseudogenes.[13]
The reason for the large number of different odor receptors is to provide a system for discriminating between as many different odors as possible. Even so, each odor receptor does not detect a single odor. Rather each individual odor receptor is broadly tuned to be activated by a number of similar odorant structures.[14][15] Analogous to the immune system, the diversity that exists within the olfactory receptor family allows molecules that have never been encountered before to be characterized. However, unlike the immune system, which generates diversity through in-situ recombination, every single olfactory receptor is translated from a specific gene; hence the large portion of the genome devoted to encoding OR genes. Furthermore most odors activate more than one type of odor receptor. Since the number of combinations and permutations of olfactory receptors is almost limitless, the olfactory receptor system is capable of detecting and distinguishing between a practically infinite number of odorant molecules.
A nomenclature system has been devised for the olfactory receptor family[16] and is the basis for the official Human Genome Project (HUGO) symbols for the genes that encode these receptors. The names of individual olfactory receptor family members are in the format "ORnXm" where:
For example OR1A1 is the first isoform of subfamily A of olfactory receptor family 1.
Members belonging to the same subfamily of olfactory receptors (>60% sequence identity) are likely to recognize structurally similar odorant molecules.[17]
Two major classes of olfactory receptors have been identified in humans:[18]
The olfactory receptor gene family in vertebrates has been shown to evolve by birth-and-death evolution, whereby new genes within the family are created through genomic events such as gene duplications or gene conversions.[19] Tandem duplications are evidenced by the fact that many olfactory receptor genes belonging to the same phylogenetic clade are located in the same gene cluster.[20] Birth-and-death evolution also involves the elimination of genes from multigene family repertoires by mutations that create nonfunctional pseudogenes. The color vision priority hypothesis states that the evolution of color vision in primates may have decreased primate reliance on olfaction, which explains the relaxation of selective pressure that accounts for the accumulation of olfactory receptor pseudogenes in primates.[21]
In 2004 Linda B. Buck and Richard Axel won the Nobel Prize in Physiology or Medicine for their work[22] on olfactory receptors.[23] In 2006 it was shown that another class of odorant receptors exist for volatile amines.[24] This class of receptors consists of the trace amine-associated receptors (TAAR) with the exception of TAAR1 which is a receptor for thyronamines.
Unfortunately, as with many other GPCRs, there is still a lack of experimental structures at atomic level for olfactory receptors and structural information is based on homology modeling methods.[25]
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