Reactome: A Curated Pathway Database

Olfactory Signaling Pathway (R-HSA-381753)

Species Homo sapiens


Mammalian Olfactory Receptor (OR) genes were discoved 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 true, and Buck and Axel received a Nobel Prize for this and subsequent work (reviewed in Keller, 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").

There are two models for GPCR-G Protein interactions: 1) ligand-GPCR binding first, then binding to G Proteins; 2) "Pre-coupling" of GPCRs and G Proteins before ligand binding {reviewed in (Oldham, 2008)}. Both models may be true for certain GPCRs in different contexts. Pre-coupling is likely to be functionally important, as pre-coupling of receptor and G Protein allows much more rapid kinetic response once ligand is bound, because the ligand-bound receptor is immediately able to transduce the signal, rather than having to diffuse around within the plasma membrane until it encounters a G Protein to interact with (Oldham, 2008).

The pre-coupling model is used here to characterise the reaction of the human ORs with G Proteins in the absence of ligand, because the ligands in humans are almost completely undocumented experimentally.

In model genetic systems such as mice, many candidate OR genes have been shown experimentally to function in olfactory signaling {reviewed in (Keller, 2008)}. For the human OR genes, experimental analysis has been much 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, 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 {reviewed in (Keller, 2008)}. In mice, essentially all olfactory signaling requires G-alpha-S (OLF), since mouse G-OLF knockouts have been shown to lack essentially all olfactory responses (Belluscio, 1998). Thus, bona fide human OR genes identified by sequence similarity (i.e., not pseudogenes with function-blocking mutations) which are known to be expressed in olfactory epithelium are expected to interact with G alpha S OLF containing G Protein trimers. Therefore, we can model the human ORs which are expressed in human olfactory epithelium as each signaling via interactions with human G-alpha-S-OLF (GNAL).

Of the 960 human OR genes and pseudogenes, there is experimental evidence which indicates that at least 437 actually are expressed in human olfactory epithelium; this includes 357 OR genes, and 80 OR pseudogenes (Zhang, 2007). These 357 olfactory-expressed OR genes are therefore expected to be functional in the Olfactory Signaling Pathway, and to interact directly with human G alpha olf in human olfactory cells.

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Compartment plasma membrane