Odorant receptors function and expression landscape
Odorant receptors (ORs) belong to the G protein-coupled receptor (GPCR) family and are the largest known mammalian gene family with around 900 genes. ORs are highly expressed by olfactory sensory neurons of the nose where they are activated by different odorant molecules which initiate a neuronal response that drives odorant discrimination and perception (Young J. and Trask B. 2002).
Higher-resolution analysis of gene expression, including q)RT-PCR, microarray, or relatively new NGS (RNASeq) analyses, have indicated that OR genes are also expressed in non-olfactory tissues including the testis, lung, intestine, skin, heart, and blood, where they can play diverse physiological roles. Although ORs expression is quite stable, the number of ORs expressed in different human tissues is highly variable from more than 60 ORs in the testis and only a few ORs in the liver (Flegel C. et al. 2013; Maßberg D. and Hatt H. 2018). OR4N4 is the most highly expressed OR in human spermatozoa and is an example of a highly and selectively expressed OR, whereas OR51E1 and OR51E2 represent ubiquitously expressed ORs, although there are highly increased in prostate tissue, especially in prostate cancer (Maßberg D. and Hatt H. 2018).
Interestingly, olfactory neurons gene expression is very peculiar, and each neuron expresses a single OR gene however, ectopic ORs expression is unlikely to be modulated by this tight mechanism with transcriptomic analysis revealing that while the majority of cancer cells express multiple ORs, tumor cells associated with the nervous system express a single OR gene type (Kalra S. et. al 2020).
Physiological functions of ectopically expressed olfactory receptors
ORs participate in important cellular processes outside of olfactory system. In the cardiovascular system, ORs have the potential to operate as the main carriers of endogenously and exogenously derived odorants in our body. OR10J5 has been proposed to be a metabolic regulator of cardiac function (Jovancevic N. et. Al 2017) and its activation promotes migration and angiogenesis (Kim S. et. al 2015). In the immune system ORs are expressed in different blood cells where aroma compounds from butter, known ligands for a variety of class I ORs, induce chemotactic behavior in human neutrophils (Geithe C. et al. 2015). OR function has been implicated in myelogenous leukemia where OR2AT4 activation leads to reduced proliferation and enhanced apoptosis of acute myeloid leukemia cells (S Manteniotis et al. 2016). In the gastrointestinal system, ORs may significantly contribute to abnormal bowel functions. In the GI tract OR ligands drive an intracellular cascade that results in enhanced serotonin release (Braun T. et. al 2007), an important regulator of gut peristalsis. In the genito-urinary system, the activation of ORs was shown to influence the motility of spermatozoa (Spehr M. et. al 2003). In the human kidney ORs elicit intracellular Ca2+flux in renal proximal tubule cells via adenylyl cyclase (AC) activity (Kalbe B et. al 2016). OR51E1 and OR51E2, initially assumed to be GPCRs only expressed in prostate tissue, play a role in prostate cancer epithelial cells proliferation via activation by β-ionone which initiates prostate cancer cell cycle arrest (Jones S. et. al 2013). In the nervous system, although there is limited data, it has been suggested that ORs adopt functions in the central nervous system. For example, OR4M1 was proposed to interfere with aberrant tau hyperphosphorylation (Zhao W. et. al 2013). In the respiratory system, the activation of ORs by amyl butyrate and bourgeonal, OR2AG1 and OR1D2 agonists, respectively, impact the contractility of human airway smooth muscle cells (Kalbe B. et. al 2016). In non-small-cell lung cancer OR2J3 activation induced apoptosis and inhibited cell proliferation and migration in long-term stimulus experiments (Kalbe B. et al. 2017). In the skin, OR51E2 was shown to play a role in human melanocyte homeostasis (Gelis L. et. al 2016) and the sandalore-activated receptor OR2AT4 shown to promote human keratinocyte proliferation and migration (Busse D. 2014).
Exploring ORs in drug discovery – opportunities and threats
Given the functional relevance of ORs in different physiological and pathophysiological contexts, primarily based on the deorphanization of these receptors, with the identified ligands being often synthetic compounds, there has been a growing interest from the scientific community to target this class of GPCRs. However, selection of promising candidates is not an easy task. Due to the diversity of the OR family it will be critical to select potential targets to modulate in a disease setting as ectopic expression of ORs does not always correlate with functionality. In addition, most ORs require olfactory-specific chaperones to be correctly targeted to the surface of heterologous cells (Maßberg D. and Hatt H. 2018) which implies that heterologous expression of ORs is generally more technically challenging compared with expression of nonolfactory GPCRs and also that deorphanization is challenging. Finally, direct evidence that ectopically expressed OR drives pathophysiological processes remains a big bottleneck.
In order to target ectopic ORs there is a need to identify selective agonists or antagonists, where the starting point can be using licensed drugs (for drug repurposing) and endogenous ligands. Odorants, the natural ligands, could potentially be used as ligands and particular forms of odorant delivery would be required where selectivity must be carefully evaluated as odoronts tend to bind to various ORs. Selective screening assays for ectopic ORs as well as investment on the structural characterization of these receptors would be of great help to aid drug discovery. The development of antibodies directed towards an OR could either drive receptor inactivation or activation of the receptor to destroy tumor cells or be used in drug delivery. The chimeric antigen receptor T cell therapy could also be a way to target tumor cells expressing ectopic ORs (Naressi R. et. al 2023).
Future directions
Important directions in ORs research to advance drug discovery include the deorphanization and characterization of relevant ligands, characterization of the function of ORs in vivo, development of in vitro systems for functional assays and the availability of structural information for structure-based drug design.
Check the original article at https://pubmed.ncbi.nlm.nih.gov/35999088/
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