Olfactory Signaling Pathway

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. 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. 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. In mice, essentially all olfactory signaling requires G-alpha-S (OLF); mouse G-OLF knockouts have been shown to lack olfactory responses. 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.

When expressed in model cell systems mammalian olfactory receptors (ORs) are typically retained in the ER and degraded by the proteasome. 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. Co-transfection of rat ORs with ODR4 enhanced the transport and expression of ORs at the cell-surface. 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. 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. 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. REEP1 and REEP5 (also known as DP1) are involved in shaping the ER by linking microtubule fibers to the ER. 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. 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. 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.

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 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.