Reactome | Olfactory Signaling Pathway

Olfactory Signaling Pathway

Stable Identifier

R-HSA-381753

DOI

10.3180/R-HSA-381753.5

Type

Pathway

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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Mammalian Olfactory Receptor (OR, also called odorant receptor) genes were discovered in rats by Linda Buck and Richard Axel, who predicted that odorants would be detected by a large family of G protein-coupled receptors (GPCRs) that are selectively expressed in the olfactory epithelium. This prediction was based on previous biochemical evidence that cAMP levels increased in olfactory neurons upon odor stimulation. These predictions proved to be accurate, and Buck and Axel received a Nobel Prize for this and subsequent work (reviewed in Keller & Vosshall 2008).
Subsequent work in mice and other vertebrates has confirmed that OR genes are comprised of a very large family of G Protein-Coupled Receptors (GPCRs) that are selectively-expressed in olfactory epithelium. Although some OR are also expressed selectively in one or a few other tissues, their expression in olfactory-epithelium generally indicates a functional role in mediating olfaction, where they couple binding by odorant ligands with intracellular olfactory signaling. (Note: the other subclasses of GPCR signaling pathways are described under "GPCR Signaling".)
The ligands for ORs are diverse, ranging from chemical compounds to peptides. Intracellular signaling by OR proteins in mice and other mammalian systems is known to be mediated via direct interactions of OR proteins with an olfactory-specific heterotrimeric G Protein, that contains an olfactory-specific G alpha protein: G alpha S OLPH (also named "GNAL").
In model genetic systems such as mice, many candidate OR genes have been shown experimentally to function in olfactory signaling (reviewed in (Keller & Vosshall 2008). For the human OR genes, experimental analysis has been more limited, although some specific OR genes, such as OR7D4 and OR11H7P have been confirmed to mediate olfactory response and signaling in humans for specific chemical odorants (Keller et al. 2007, Abbafy 2007). Mice and other rodents are believed to have about 1000 functional OR genes, as well as many additional pseudogenes. Based on sequence similarities, there are 960 human OR genes, but approximately half of these are pseudogenes (Keller 2008). In mice, essentially all olfactory signaling requires G-alpha-S (OLF); mouse G-OLF knockouts have been shown to lack olfactory responses (Belluscio 1998). Bona fide human OR genes identified by sequence similarity (not pseudogenes with function-blocking mutations) that are expressed in olfactory epithelium are expected to interact with G alpha S OLF containing G Protein trimers.
Of the 960 human OR genes and pseudogenes, there is experimental evidence that indicates over 430 are expressed in human olfactory epithelium, including 80 expressed OR pseudogenes (Zhang 2007).
When expressed in model cell systems mammalian olfactory receptors (ORs) are typically retained in the ER and degraded by the proteasome (McClintock et al. 1997). A study using Caenorhabditis elegans showed that the transport of ORs to the cilia of olfactory neurons required the expression and association of ORs with a transmembrane protein, ODR4 (Dwyer et al. 1998). Co-transfection of rat ORs with ODR4 enhanced the transport and expression of ORs at the cell-surface (Gimelbrant et al. 2001). These studies suggested that olfactory neurons might have a selective molecular machinery that promotes expression of ORs at the cells surface. Two human protein families have been identified as potential accessory proteins involved in the trafficking of ORs to the plasma membrane (Saito et al. 2004). Receptor transporting proteins 1 and 2 (RTP1, RTP2) both strongly induced expression of several ORs at the cell-surface. To a lesser extent, the receptor expression enhancing protein 1 (REEP1) also promoted cell-surface expression. These proteins are specifically expressed in olfactory neurons with no expression in testis, where a subset of ORs are expressed (Parmentier et al. 1992, Spehr et al. 2003). Other members of the RTP and REEP families have a widespread distribution. RTP3 and RTP4 have been shown to promote cell-surface expression of the bitter taste receptors, TAS2Rs (Behrens et al. 2006). REEP1 and REEP5 (also known as DP1) are involved in shaping the ER by linking microtubule fibers to the ER (Park et al. 2010, Voeltz et al. 2006). A recent study looking at the role of REEP in the trafficking of Alpha2A- and Alpha2C-adrenergic receptors showed that REEP1-2 and 6 enhance the cell-surface expression of Alpha2C, but not Alpha2A, by increasing the capacity of ER cargo, thereby allowing more receptors to reach the cell-surface (Bjork et al. 2013). Unlike RTP1, REEP1-2 and 6 are only present in the ER, do not traffic to the plasma membrane and specifically interact with the minimal/non-glycosylated forms of Alpha2C via an interaction with its C-terminus (Saito et al. 2004, Bjork et al. 2013). REEPs may function as general modulators of the ER, rather than specifically interacting with GPCRs. Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia (Esteves et al. 2014).
Olfactory receptors (ORs, also called odorant receptors) are present on the plasma membrane of cilia of olfactory sensory neurons located in the olfactory epithelium of the nasal sinus. Each mature neuron expresses only one OR gene (reviewed in Nagai et al. 2016) and each OR binds one particular volatile chemical or set of volatile chemicals, known as odorants. The binding of an odorant to an OR (Mainland et al. 2015) causes a conformational change in the receptor that activates the G alpha subunit (Golf, GNAL) of an associated heterotrimeric G protein complex to exchange GDP for GTP (inferred from mouse homologs in Jones et al. 1990). GNAL:GTP and the Gbeta:Ggamma subcomplex (GNB1:GNG13) dissociate from the olfactory receptor and GNAL:GTP then binds and activates adenylate cyclase 3 (ADCY3) (inferred from rat homologs in Bakalyar and Reed 1990, reviewed in Boccaccio et al. 2021). Cyclic AMP produced by ADCY3 binds and opens the olfactory cyclic nucleotide-gated channel (CNG channel) composed of CNGA2, CNGA4, and CNGB isoform 1b (inferred from rat homologs in Liman and Buck 1994). The CNG channel translocates sodium and calcium cations from the extracellular region into the cytosol. The resulting cytosolic calcium ions bind ANO2 and increase the transport of chloride ions by ANO2 from the cytosol to the extracellular region (inferred from mouse homologs in Pifferi et al. 2009, Stephan et al. 2009). The translocations of ions across the plasma membrane causes depolarization of the neuron yielding a receptor potential and action potential that is transmitted to the olfactory bulb of the brain.

Literature References

PubMed ID	Title	Journal	Year
1370859	Expression of members of the putative olfactory receptor gene family in mammalian germ cells Parmentier, M, Libert, F, Schurmans, S, Schiffmann, S, Lefort, A, Eggerickx, D, Ledent, C, Mollereau, C, Gerard, C, Perret, J	Nature	1992
18938244	Better smelling through genetics: mammalian odor perception Keller, A, Vosshall, LB	Curr Opin Neurobiol	2008
17509148	Characterizing the expression of the human olfactory receptor gene family using a novel DNA microarray Zhang, X, De la Cruz, O, Pinto, JM, Nicolae, D, Firestein, S, Gilad, Y	Genome Biol	2007
27587538	Monogenic and Monoallelic Expression of Odorant Receptors Nagai, MH, Armelin-Correa, LM, Malnic, B	Mol Pharmacol	2016
18043707	Heterotrimeric G protein activation by G-protein-coupled receptors Oldham, WM, Hamm, HE	Nat Rev Mol Cell Biol	2008
2105931	Biochemical characterization of three stimulatory GTP-binding proteins. The large and small forms of Gs and the olfactory-specific G-protein, Golf Jones, DT, Masters, SB, Bourne, HR, Reed, RR	J Biol Chem	1990
2255909	Identification of a specialized adenylyl cyclase that may mediate odorant detection Bakalyar, HA, Reed, RR	Science	1990
19561302	ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification Stephan, AB, Shum, EY, Hirsh, S, Cygnar, KD, Reisert, J, Zhao, H	Proc Natl Acad Sci U S A	2009
17873857	Genetic variation in a human odorant receptor alters odour perception Keller, A, Zhuang, H, Chi, Q, Vosshall, LB, Matsunami, H	Nature	2007
9590179	Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel membrane-associated protein Dwyer, ND, Troemel, ER, Sengupta, P, Bargmann, CI	Cell	1998
24098485	REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity Björk, S, Hurt, CM, Ho, VK, Angelotti, T	PLoS ONE	2013
24388663	Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia Esteves, T, Durr, A, Mundwiller, E, Loureiro, JL, Boutry, M, Gonzalez, MA, Gauthier, J, El-Hachimi, KH, Depienne, C, Muriel, MP, Acosta Lebrigio, RF, Gaussen, M, Noreau, A, Speziani, F, Dionne-Laporte, A, Deleuze, JF, Dion, P, Coutinho, P, Rouleau, GA, Züchner, S, Brice, A, Stevanin, G, Darios, F	Am. J. Hum. Genet.	2014
33447881	The cyclic AMP signaling pathway in the rodent main olfactory system Boccaccio, A, Menini, A, Pifferi, S	Cell Tissue Res	2021
11060288	Olfactory receptor trafficking involves conserved regulatory steps Gimelbrant, AA, Haley, SL, McClintock, TS	J. Biol. Chem.	2001
25977809	Human olfactory receptor responses to odorants Mainland, JD, Li, YR, Zhou, T, Liu, WL, Matsunami, H	Sci Data	2015
20200447	Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network Park, SH, Zhu, PP, Parker, RL, Blackstone, C	J. Clin. Invest.	2010
16720576	Members of RTP and REEP gene families influence functional bitter taste receptor expression Behrens, M, Bartelt, J, Reichling, C, Winnig, M, Kuhn, C, Meyerhof, W	J. Biol. Chem.	2006
16469703	A class of membrane proteins shaping the tubular endoplasmic reticulum Voeltz, GK, Prinz, WA, Shibata, Y, Rist, JM, Rapoport, TA	Cell	2006
15550249	RTP family members induce functional expression of mammalian odorant receptors Saito, H, Kubota, M, Roberts, RW, Chi, Q, Matsunami, H	Cell	2004
17973576	Genetic elucidation of human hyperosmia to isovaleric acid Menashe, I, Abaffy, T, Hasin, Y, Goshen, S, Yahalom, V, Luetje, CW, Lancet, D	PLoS Biol	2007
19475416	TMEM16B induces chloride currents activated by calcium in mammalian cells Pifferi, S, Dibattista, M, Menini, A	Pflugers Arch	2009
1840504	A novel multigene family may encode odorant receptors: a molecular basis for odor recognition Buck, L, Axel, R	Cell	1991
7522482	A second subunit of the olfactory cyclic nucleotide-gated channel confers high sensitivity to cAMP Liman, ER, Buck, LB	Neuron	1994
9459443	Mice deficient in G(olf) are anosmic Belluscio, L, Gold, GH, Nemes, A, Axel, R	Neuron	1998
14983052	The human olfactory receptor gene family Malnic, B, Godfrey, PA, Buck, LB	Proc Natl Acad Sci U S A	2004
9332724	Functional expression of olfactory-adrenergic receptor chimeras and intracellular retention of heterologously expressed olfactory receptors McClintock, TS, Landers, TM, Gimelbrant, AA, Fuller, LZ, Jackson, BA, Jayawickreme, CK, Lerner, MR	Brain Res. Mol. Brain Res.	1997
16402120	Heterotrimeric G-proteins: a short history Milligan, G, Kostenis, E	Br J Pharmacol	2006