Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Olfactory Receptors

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_120


Historical Background

Among the five senses, smell is unique in that it is dedicated to discriminating an enormous diversity of stimulating ligands. Olfactory sensory neurons achieve this detection by the expression of a multigene family of seven-transmembrane G protein–coupled receptors (GPCRs) originally identified by Linda Buck and Richard Axel (1991). These receptors, termed olfactory receptors (OR, plural ORs), are expressed in the olfactory tissue of all terrestrial vertebrates examined thus far, and have been shown to respond directly to odorant binding. The identification and subsequent study of ORs has provided great insight into the molecular and neuronal organization of the olfactory system. Indeed, in 2004, Buck and Axel were jointly awarded the Nobel Prize in Physiology for their pioneering work in odorant receptor discovery. Most of the current understanding of ORs results from experiments from the mouse model which is the focus of this review.

General Physiology and Classification of ORs

Olfactory sensory neurons reside in the main olfactory epithelium (MOE) which is located in the distal recess of the nasal cavity. The MOE covers the evaginated nasal terbinates resulting in increased surface capacity to sample ligands. The dendrite of each olfactory neuron projects toward the nasal lumen providing direct sensory contact with the odor environment. The dendrite is tufted with 20–30 sensory cilia and OR proteins localized to these cilia membranes further increase surface exposure to the ligand environment. Active sniffing draws odorant ligands into the nasal cavity enabling binding and subsequent activation of ORs. Each odorant receptor is expressed from a single coding gene. Together, individual odorant receptor genes comprise the largest GPCR family in the mammalian genome (in the human genome they account for approximately 3% of predicted exons). ORs belong to class A GPCRs (Rhodopsin family) and can be broadly divided into classes I and II (Zhang and Firestein 2002). Class I is highly conserved across evolution; related to chemosensory receptors in fish. Sequence analysis shows class II to be more divergent, suggesting that this OR class may have evolved to provide specific ecological adaptations.

Evolution of Odorant Receptors

Comparative genomics has revealed that the odorant receptor family shows rapid gene birth and death events across evolution. Tandem gene duplications have resulted in chromosomal clusters of closely related ORs with high sequence homology and similar ligand-binding profiles. In the mouse, there are 43 odorant receptor clusters found on every chromosome. Old world primates, including humans, have a significantly smaller OR repertoire (390 putatively functional genes) compared to other sequenced vertebrates such as mice (1,468 putatively functional genes), rats (1,750 putatively functional genes), and dogs (922 putatively functional genes). The evolutionary loss of functional OR coding regions has been attributed to the correlated evolution of trichromatic vision and an increased utilization of visual stimuli.

OR-Mediated Signal Transduction

Upon ligand stimulation, odorant receptors initiate a signal transduction cascade that results in neuron depolarization and transmission of the signal to the brain (Fig. 1). In most olfactory sensory neurons, detection of a cognate odor ligand alters the confirmation of the OR to activate a specialized heterotrimeric  guanine nucleotide binding protein (Gαolf)(Bakalyar and Reed 1991; Dhallan et al. 1990; Jones and Reed 1989) which converts guanosine tri phosphate (GTP) to guanosine di phosphate (GDP). GTP-bound Gαolf stimulates adenylate cyclase III (ACIII) to produce secondary messenger cyclic adenosine monophosphate (cAMP); and cAMP regulates a heteromeric calcium channel composed of cyclic nucleotide gated (CNG) channels alpha 2 (CNGA2), alpha 4 (CNGA4), and beta 1b (CNGB1b) to permit entry of calcium ions. Calcium entry subsequently gates a chloride channel resulting in the efflux of chloride ions to depolarize the sensory neuron (Brunet et al. 1996; Song et al. 2008). Neural depolarization transmits the sensory signal to second-order neurons in the olfactory bulb in the brain. In addition to these canonical mechanisms, there are specialized subsets of sensory neurons in the MOE that alternatively signal through the transient receptor potential channel (TrpM5), or utilize cyclic guanidyl mono phosphate(cGMP) produced by the expression and activation of a membrane-receptor guanylyl-cyclase (GC-D). The smell of an odor is rapidly sensitizing. This is due, in part, to signaling events in the sensory neuron as activated olfactory signal transduction molecules are targeted for negative feedback regulation. Calcium and calcium-binding protein, calmodulin (CaM), bind and close the CNG channels. Calcium/Calmodulin (Ca/CaM)-dependent protein kinase II phosphorylates ACIII, reducing cAMP production. Desensitization of the odorant receptors appears to occur through phosphorylation by G protein–coupled receptor kinase 3 (GRK3) interaction with β-arrestin2 (Mashukova et al. 2006).
Olfactory Receptors, Fig. 1

Endogenous G protein signaling and desensitization pathway activated by odorant receptors on odor binding. Signaling: On binding an odor molecule, the odorant receptor activates the Gαolf, which stimulates ACIII to generate cyclic AMP. cAMP regulates ion channel CNG to allow influx of sodium and calcium ions. Calcium ions in turn regulate a chloride channel to induce efflux of chloride ions. Influx and efflux of the said ions result in depolarization of the olfactory sensory neuron. Desensitization: Calcium and calcium-binding proteins like calmodulin CaM act as feedback inhibitors of OR-induced signaling by (a) binding and blocking CNG or (b) inducing PKII to phosphorylate and inhibit ACII. GRK3 may phosphorylate the odorant receptor so it can now bind β arrestin for desensitization and internalization

Olfactory Receptor Choice: The Singularity of OR Gene Expression

A remarkable property of the olfactory system is the ability to detect and distinguish among a seemingly endless variety of odor molecules. To achieve this precise discrimination, each individual olfactory sensory neuron expresses only one of the many OR genes present in the genome. Indeed this has been referred to as the “one neuron-one receptor” rule. Expression of a single OR dedicates each sensory neuron is responsive only to the cognate ligands of the expressed receptor, and sensory neurons that express different receptors display differential response profiles to odor ligands. The mechanisms that enable a neuron to activate the expression of a single receptor, and additionally silence all other OR loci distributed across the genome, are only partially understood. Recent whole genome chromatin immunoprecipitation analysis suggests that MOE neurons initially employ a distinct type of methylation of OR loci to generate heterochromatin silencing of all ORs. In a second step, one receptor reverses this silencing. The choice of which particular OR gene will be expressed in each neuron is thought to be largely a random process. However, each OR is restricted to a stereotypic expression “zone” in the MOE which may be regulated by zone-specific transcription factors. OR genes are polyallelic, and analysis of the expression of maternal and paternal genes have revealed that only one allele is expressed per neuron. This allelic exclusion simplifies the mechanistic challenge of coordinating receptor activation between both alleles and further increases the ability of genetic variation to functionally diversify odorant detection. Activation of the chosen receptor requires physical interaction of the OR promoter with a cis-acting locus control region (LCR). For one of the OR clusters, containing mouse olfactory receptor28 (MOR28), the LCR known as the “H-region,” was identified as a 2.1 kb noncoding sequence that is evolutionary conserved between mouse and human. Deletion of the H-region abolishes the expression of MOR28 OR genes. Other LCRs that act in cis to regulate the expression of ORs within a cluster, or in trans to coordinate receptor choice across the genome, are still largely unknown. Additional experiments with transgenes have shown that if the chosen receptor cannot produce a functional protein (either through a frameshift or a deleltion) a second receptor will be activated. This suggests that the OR protein itself generates a negative feedback signaling to ultimately repress the activation of additional ORs. How functional ORs repress expression of additional ORs in olfactory sensory neurons remains unknown as mutating an ORs ability to activate G-protein mediated signaling has no effect on OR negative feedback regulation. Future experiments will be necessary to uncover the mechanisms that stabilize the expression of one receptor.

Role of ORs in Axon Pathfinding

Olfactory sensory neurons that express the same OR converge in specific neuropil, called glomeruli, in the olfactory bulb in the brain. Sensory neurons use both dorsal/ventral and anterior/posterior coordinates to direct their axons to the correct glomeruli. While the general process of receptor choice is stochastic, each OR is expressed in a stereotypic “zone” within the olfactory epithelium. The mechanisms that regulate this zonally restricted anatomic organization have not been identified; however, the positional organization of ORs correlates with the expression of complementary gradients of guidance molecules including Robo-2, Neuropilin-2 (Nrp2), and Sema-3f in the sensory neurons. Corresponding gradients of Slit-1 and Slit-3 are present in the olfactory bulb thereby creating a topographic organization of glomeruli along the dorsal/ventral axis that mirrors the general spatial organization of ORs in the MOE (Cho et al. 2007).

In contrast to these genetically determined mechanisms, an elegant series of experiments has shown involvement of an activity driven mechanism, signaling from the OR itself, to direct anterior/posterior axon guidance. The first indication of this arose from generation of mice in which pairs of genomic OR coding regions were swapped. These mutant mice displayed OR-driven mis-localization of their glomeruli. Moreover, OR protein was found to be localized to the axon terminus; a pivotal position to direct axon guidance. How do ORs guide axons? Key insights came from the observation that ORs mutant in Gs signaling failed to form proper glomeruli. Complementary studies of constitutively active Gs and PKA mutants indicate that high levels of OR-mediated cAMP directs axons to the posterior, while low cAMP levels directs axons to the anterior. cAMP levels directly correspond to the transcription of neuropilin-1 (Nrp1) an axon guidance molecule. Nrp1 and Sema3A expression levels form complementary anterior/posterior gradients in olfactory neurons. Axon–axon interactions are thought to sort and organize neurons as they develop toward their targets (Imai et al. 2009). While these mechanisms account for general axon targeting, it is thought that OR-mediated cAMP signaling additionally further refines glomerular patterning. Levels of neuronal activity regulate additional sets of axon guidance and adhesion molecules including Kirrel2, Kirrel3, EphA5, and ephrin-A. The repulsive and adhesive effects of these molecules are thought to promote homotypic formation of individual glomeruli (Serizawa et al. 2006). The mechanism of how individual ORs generate differential levels of cAMP activity that can distinguish the position of neighboring glomeruli remains to be understood.

The Combinatorial Code of ORs to Encode Odor Identity

How do the repertoire of ORs (390 in humans or 1,468 in mice) discriminate a seemingly endless array of odor ligands? Elegant experiments have shown that ORs can respond to a variety of structurally distinct odor molecules (Fig. 2) (Malnic et al. 1999). Each neuron (and therefore OR) is not tuned to the entire ligand per se, but instead is responsive to molecular features of the given ligand, such as the carbon chain length or functional group components of the odor molecule. Therefore, an individual OR can detect many ligands that differ in overall structure as long as they share a common molecular feature recognized by the OR. Moreover, this principle results in each ligand activating multiple receptors each able to bind different features of the molecule’s overall structure. Pure ligands have been shown to activate approximately 10% of the expressed ORs. This distributed activity is referred to as the “combinatorial code” of odor processing. Assuming that the OR repertoire is able to detect a large variety of molecular features, this strategy would enable the detection of potentially unlimited number of odor molecules. The combinatorial coding strategy immediately deconstructs each odorant at the sensory receptor interface and because this information is separated into anatomically distinct glomeruli in the olfactory bulb, each odorant generates multiple lines of distinct activity processed in parallel. How this information is ultimately bound into an odor percept is still unknown.
Olfactory Receptors, Fig. 2

Combinatorial receptor codes for odors. Green tick mark shows receptors (top panel) that recognize odorants (left panel). The identity of each odor molecule is encoded by a unique combination of receptors. Each receptor can act as one component of the combinatorial code for more than one odor molecule. This model allows for the recognition and discrimination of almost unlimited number and variety of odor molecules

Other Olfactory Receptors

In addition to the ORs, the main olfactory epithelium also expresses a family of trace amine receptors (TAARs) which have been shown to detect volatile amines (Liberles and Buck 2006). Additionally most vertebrates have an accessory olfactory system, the vomeronasal organ (VNO), which is physiologically and morphologically distinct from the main olfactory epithelium. The VNO has been shown to express at least three classes of chemosensory receptors that are evolutionarily distinct both from the odorant receptors and from each other: vomeronasal receptors class I (V1Rs, Vmn1Rs) (Dulac and Axel 1995), vomeronasal receptors class II (V2Rs, Vmn2Rs) (Herrada and Dulac 1997; Matsunami and Buck 1997; Ryba and Tirindelli 1997), and formyl peptide receptors (FPRs) (Liberles et al. 2009; Riviere et al. 2009). GPCRs expressed in the VNO are thought to largely detect volatile and peptide pheromonal ligands that mediate social behaviors like courtship, territorial aggression, gender and individual recognition, maternal aggression, and interspecies defense (Bean and Wysocki 1989; Chamero et al. 2007; Del Punta et al. 2002; Haga et al. 2010; Kimoto et al. 2005; Leinders-Zufall et al. 2000; Papes et al. 2010; Wysocki and Lepri 1991).


Environmental odor cues are detected by hundreds of seven-membrane-spanning odorant receptors, expressed in the olfactory system. These olfactory receptors can be broadly classified into type I and type II, type I being evolutionarily more ancient and conserved. On binding odors, ORs can signal through a canonical pathway involving cAMP second messenger that regulates the activity of the CNG channel, depolarizing the neurons. Additionally there are other noncanonical signal transductions involving TrpM5 or cGMP. Each olfactory neuron expresses a specific receptor and activation of different combinations of receptors by an odor or mixture of odors helps an organism to distinguish an endless repertoire of chemicals.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Cell BiologyThe Scripps Research InstituteLa JollaUSA