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Olfactory receptor


Olfactory receptor

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]


  • Expression 1
  • Mechanism 2
  • Diversity 3
  • Families 4
  • Evolution 5
  • Discovery 6
  • See also 7
  • References 8
  • External links 9



  • Olfactory Receptor Database
  • Human Olfactory Receptor Data Exploratorium (HORDE)
  • Olfactory Receptor Protein at the US National Library of Medicine Medical Subject Headings (MeSH)

External links

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  9. ^ Saberi M, Seyed-allaei (2015). "Olfactory receptors are sensitive to molecular volume of odorants". bioRxiv.  
  10. ^ Jones DT, Reed RR (May 1989). "Golf: an olfactory neuron specific-G protein involved in odorant signal transduction". Science 244 (4906): 790–5.  
  11. ^ de March, Claire A.; Kim, Soo-Kyung; Antonczak, Serge; Goddard, William A. III; Golebiowski, Jérôme (September 2015). "G protein-coupled odorant receptors: From sequence to structure". Protein Science 24 (9): 1543-1548.  
  12. ^ de March, Claire A.; Yu, Yiqun; Ni, Mengjue J.; Adipietro, Kaylin A.; Hiroaki, Matsunami; Ma, Minghong; Golebiowski, Jérôme (June 29, 2015). "Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors". Journal of the American Chemical Society 137 (26): 8611–8616.  
  13. ^ Wang J, Luthey-Schulten ZA, Suslick KS (Mar 2003). "Is the olfactory receptor a metalloprotein?". Proceedings of the National Academy of Sciences of the United States of America 100 (6): 3035–9.  
  14. ^ Crabtree RH (1978). "Copper (I): A possible olfactory binding site". Journal of Inorganic and Nuclear Chemistry 40 (7): 1453.  
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  21. ^ Vosshall LB (May 2015). "Laying a controversial smell theory to rest". Proceedings of the National Academy of Sciences of the United States of America 112 (21): 6525–6.  
  22. ^ Everts S (2015). "Receptor Research Reignites A Smelly Debate". Chemical & Engineering News 93 (18): 29–30. 
  23. ^ Turin L, Gane S, Georganakis D, Maniati K, Skoulakis EM (Jun 2015). "Plausibility of the vibrational theory of olfaction". Proceedings of the National Academy of Sciences of the United States of America 112 (25): E3154.  
  24. ^ Block E, Jang S, Matsunami H, Batista VS, Zhuang H (Jun 2015). "Reply to Turin et al.: Vibrational theory of olfaction is implausible". Proceedings of the National Academy of Sciences of the United States of America 112 (25): E3155.  
  25. ^ Gilad Y, Lancet D (Mar 2003). "Population differences in the human functional olfactory repertoire". Molecular Biology and Evolution 20 (3): 307–14.  
  26. ^ Malnic B, Hirono J, Sato T, Buck LB (Mar 1999). "Combinatorial receptor codes for odors". Cell 96 (5): 713–23.  
  27. ^ Araneda RC, Peterlin Z, Zhang X, Chesler A, Firestein S (Mar 2004). "A pharmacological profile of the aldehyde receptor repertoire in rat olfactory epithelium". The Journal of Physiology 555 (Pt 3): 743–56.  
  28. ^ Smith R, Peterlin Z, Araneda R (2013). Pharmacology of Mammalian Olfactory Receptors. Olfactory Receptors Methods in Molecular Biology: Humana Press. pp. 203–209.  
  29. ^ de March, Claire A.; Ryu, SangEun; Sicard, Gilles; Moon, Cheil; Golebiowski, Jérôme (September 2015). "Structure–odour relationships reviewed in the postgenomic era". Flavour and Fragrance Journal 30 (5): 342-361.  
  30. ^ Glusman G, Bahar A, Sharon D, Pilpel Y, White J, Lancet D (Nov 2000). "The olfactory receptor gene superfamily: data mining, classification, and nomenclature". Mammalian Genome 11 (11): 1016–23.  
  31. ^ Malnic B, Godfrey PA, Buck LB (Feb 2004). "The human olfactory receptor gene family". Proceedings of the National Academy of Sciences of the United States of America 101 (8): 2584–9.  
  32. ^ Glusman G, Yanai I, Rubin I, Lancet D (May 2001). "The complete human olfactory subgenome". Genome Research 11 (5): 685–702.  
  33. ^ Nei M, Rooney AP (2005). "Concerted and birth-and-death evolution of multigene families". Annual Review of Genetics 39: 121–52.  
  34. ^ Niimura Y, Nei M (2006). "Evolutionary dynamics of olfactory and other chemosensory receptor genes in vertebrates". Journal of Human Genetics 51 (6): 505–17.  
  35. ^ Niimura Y, Nei M (Feb 2005). "Comparative evolutionary analysis of olfactory receptor gene clusters between humans and mice". Gene 346 (6): 13–21.  
  36. ^ Nozawa M, Nei M (2008). "Genomic drift and copy number variation of chemosensory receptor genes in humans and mice". Cytogenetic and Genome Research 123 (1-4): 263–9.  
  37. ^ a b c Niimura Y, Nei M (2007). "Extensive gains and losses of olfactory receptor genes in mammalian evolution". PloS One 2 (8): e708.  
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  39. ^ Craven BA, Paterson EG, Settles GS (Jun 2010). "The fluid dynamics of canine olfaction: unique nasal airflow patterns as an explanation of macrosmia". Journal of the Royal Society, Interface / the Royal Society 7 (47): 933–43.  
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  42. ^ Niimura Y (Apr 2012). "Olfactory receptor multigene family in vertebrates: from the viewpoint of evolutionary genomics". Current Genomics 13 (2): 103–14.  
  43. ^ Pierron D, Cortés NG, Letellier T, Grossman LI (Feb 2013). "Current relaxation of selection on the human genome: tolerance of deleterious mutations on olfactory receptors". Molecular Phylogenetics and Evolution 66 (2): 558–64.  
  44. ^ Buck L, Axel R (Apr 1991). "A novel multigene family may encode odorant receptors: a molecular basis for odor recognition". Cell 65 (1): 175–87.  
  45. ^ "Press Release: The 2004 Nobel Prize in Physiology or Medicine". Retrieved 2007-06-06. 
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See also

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.[49]

In 2004 Linda B. Buck and Richard Axel won the Nobel Prize in Physiology or Medicine for their work[44] on olfactory receptors.[45] In 2006 it was shown that another class of odorant receptors exist for volatile amines.[46] This class of receptors consists of the trace amine-associated receptors (TAAR), including the primary biomolecular target of amphetamine and its endogenous analogues, TAAR1.[47][48] 3-Iodothyronamine, a thyroid hormone, is also known to activate the receptor.[47]


It has been shown that negative selection is still relaxed in modern human olfactory receptors, suggesting that no plateau of minimal function has yet been reached in modern humans and therefore that olfactory capability might still be decreasing. This is considered to provide a first clue to the future human genetic evolution.[43]

Compared to many other mammals, primates have a relatively small number of functional OR genes. For instance, since divergence from their most recent common ancestor (MRCA), mice have gained a total of 623 new OR genes, and lost 285 genes, whereas humans have gained only 83 genes, but lost 428 genes.[37] Mice have a total of 1035 OR genes, humans have 387 OR genes.[37] The 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.[38] However, recent evidence has rendered the vision priority hypothesis obsolete, because it was based on misleading data and assumptions. The hypothesis assumed that functional OR genes can be correlated to the olfactory capability of a given animal.[38] In this view, a decrease in the fraction of functional OR genes would cause a reduction in the sense of smell; species with higher pseudogene count would also have a decreased olfactory ability. This assumption is flawed. Dogs, which are reputed to have good sense of smell,[39] do not have the largest number of functional OR genes.[37] Additionally, pseudogenes may be functional; 67% of human OR pseudogenes are expressed in the main olfactory epithelium, where they possibly have regulatory roles in gene expression.[40] More importantly, the vision priority hypothesis assumed a drastic loss of functional OR genes at the branch of the OWMs, but this conclusion was biased by low-resolution data from only 100 OR genes.[41] High-resolution studies instead agree that primates have lost OR genes in every branch from the MRCA to humans, indicating that the degeneration of OR gene repertories in primates cannot simply be explained by the changing capabilities in vision.[42]

[36] has brought together segments from several OR genes to generate and degenerate odorant binding site configurations, creating new functional OR genes as well as pseudogenes.birth-and-death evolution Such [35] The olfactory receptor gene family in vertebrates has been shown to evolve through genomic events such as


  • class I (fish-like receptors) OR families 51-56
  • class II (tetrapod specific receptors) OR families 1-13

Two major classes of olfactory receptors have been identified in humans:[32]

Members belonging to the same subfamily of olfactory receptors (>60% sequence identity) are likely to recognize structurally similar odorant molecules.[31]

For example, OR1A1 is the first isoform of subfamily A of olfactory receptor family 1.

  • OR is the root name (Olfactory Receptor superfamily)
  • n = an integer representing a family (e.g., 1-56) whose members have greater than 40% sequence identity,
  • X = a single letter (A, B, C, ...) denoting a subfamily (>60% sequence identity), and
  • m = an integer representing an individual family member (isoform).

A HUGO) symbols for the genes that encode these receptors. The names of individual olfactory receptor family members are in the format "ORnXm" where:


Deorphanization of odor receptors can be completed using electrophysiological and imaging techniques to analyze the response profiles of single sensory neurons to odor repertoires.[28] Such data open the way to the deciphering of the combinatorial code of the perception of smells.[29]

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.[26][27] 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.

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 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.[25]


It has been claimed that human olfactory receptors are capable of distinguishing between deuterated and undeuterated human embryonic kidney cells doesn't adequately reconstitute the complex nature of olfaction...". In response, the authors of the second study state "Embryonic kidney cells are not identical to the cells in the nose .. but if you are looking at receptors, it's the best system in the world."[22][23][24]

It should be noted, however, that deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0 °C for H2O vs. 101.42 °C for D2O; melting points: 0.0 °C for H2O, 3.82 °C 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.[18]

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.[16] 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).[17] 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.

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. Their sequences exhibit typical class A GPCR motifs, useful for building their structures with molecular modeling.[11] Golebiowski, Ma and Matsunami showed that the mechanism of ligand recognition, although similar to other non-olfactory class A GPCRs, involves residues specific to olfactory receptors, notably in the sixth helix.[12] There is a highly conserved sequence in roughly three quarters of all ORs that is a tripodal metal ion binding site,[13] 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. Crabtree, in 1978, had previously suggested that Cu(I) is "the most likely candidate for a metallo-receptor site in olfaction" for strong-smelling volatiles which are also good metal-coordinating ligands, such as thiols.[14] Zhuang, Matsunami and Block, in 2012, confirmed the Crabtree/Suslick proposal for the specific case of a mouse OR, MOR244-3, showing that copper is essential for detection of certain thiols and other sulfur-containing compounds. Thus, by using a chemical that binds to copper in the mouse nose, so that copper wasn’t available to the receptors, the authors showed that the mice couldn't detect the thiols. However, these authors also found that MOR244-3 lacks the specific metal ion binding site suggested by Suslick, instead showing a different motif in the EC2 domain.[15]

Rather than binding specific ligands, 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,[8] which depend on physio-chemical properties of molecules like their molecular volumes .[9] 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)[10] 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.


[7].egg cell to find the chemotaxis cells also express odor receptors, which are thought to be involved in Sperm [6]

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