Human Olfactory Receptors: Novel Cellular Functions Outside of the Nose, 2018, Maßberg et al

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Human Olfactory Receptors: Novel Cellular Functions Outside of the Nose

Maßberg, Désirée; Hatt, Hanns

Abstract
Olfactory receptors (ORs) are not exclusively expressed in the olfactory sensory neurons; they are also observed outside of the olfactory system in all other human tissues tested to date, including the testis, lung, intestine, skin, heart, and blood. Within these tissues, certain ORs have been determined to be exclusively expressed in only one tissue, whereas other ORs are more widely distributed in many different tissues throughout the human body. For most of the ectopically expressed ORs, limited data are available for their functional roles. They have been shown to be involved in the modulation of cell-cell recognition, migration, proliferation, the apoptotic cycle, exocytosis, and pathfinding processes. Additionally, there is a growing body of evidence that they have the potential to serve as diagnostic and therapeutic tools, as ORs are highly expressed in different cancer tissues. Interestingly, in addition to the canonical signaling pathways activated by ORs in olfactory sensory neurons, alternative pathways have been demonstrated in nonolfactory tissues. In this review, the existing data concerning the expression, as well as the physiological and pathophysiological functions, of ORs outside of the nose are highlighted to provide insights into future lines of research.

Web | DOI | Physiological Reviews
 
I became interested in olfactory receptors as a couple of related genes (OR5V1 OR5AC2) cropped up in the PrecisionLife candidate genes and were flagged in one of the clusters in the analysis I was doing.

It may not be significant, but it’s interesting. They are used for far more than smelling…

In vertebrates, the olfactory receptors are located in both the cilia and synapses of the olfactory sensory neurons and in the epithelium of the human airway. Sperm cells also express odorant receptors, which are thought to be involved in chemotaxis to find the egg cell.
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en.wikipedia.org

Olfactory receptor - Wikipedia

en.wikipedia.org en.wikipedia.org
 
Rather than starting another thread, this is one of the papers quoted, and one of many from the Pluznick Lab at Johns Hopkins, here’s a list of their publications in this area and a quote from their website

G protein-coupled receptors (GPCRs) play important roles in helping the kidney to maintain homeostasis, but, there are many GPCRs which are well-expressed in the kidney but do not have a known functional role. We are interested in uncovering the roles of these “understudied” renal GPCRs. Many of these receptors are “chemosensory” GPCRs – olfactory or taste receptors – thus, we are working to understand how the kidney leverages these powerful chemosensors to help support kidney function. Several of the receptors we study are also expressed in the cardiovascular system, and thus we are also interested in how these receptors help to modulate cardiovascular function.
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Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation

Pluznick, Jennifer L.; Protzko, Ryan J.; Gevorgyan, Haykanush; Peterlin, Zita; Sipos, Arnold; Han, Jinah; Brunet, Isabelle; Wan, La-Xiang; Rey, Federico; Wang, Tong; Firestein, Stuart J.; Yanagisawa, Masashi; Gordon, Jeffrey I.; Eichmann, Anne; Peti-Peterdi, Janos; Caplan, Michael J.

Abstract
Olfactory receptors are G protein-coupled receptors that mediate olfactory chemosensation and serve as chemosensors in other tissues. We find that Olfr78, an olfactory receptor expressed in the kidney, responds to short chain fatty acids (SCFAs). Olfr78 is expressed in the renal juxtaglomerular apparatus, where it mediates renin secretion in response to SCFAs. In addition, both Olfr78 and G protein-coupled receptor 41 (Gpr41), another SCFA receptor, are expressed in smooth muscle cells of small resistance vessels. Propionate, a SCFA shown to induce vasodilation ex vivo, produces an acute hypotensive response in wild-type mice. This effect is differentially modulated by disruption of Olfr78 and Gpr41 expression. SCFAs are end products of fermentation by the gut microbiota and are absorbed into the circulation. Antibiotic treatment reduces the biomass of the gut microbiota and elevates blood pressure in Olfr78 knockout mice. We conclude that SCFAs produced by the gut microbiota modulate blood pressure via Olfr78 and Gpr41.

Web | DOI | PMC | PDF | Proceedings of the National Academy of Sciences
 
It would!

OLFM4 isn’t even in the PrecisionLife gene list. Only CSE1L and DCC are in both I think. Not sure what to make of that or if it’s worth looking at a combined gene set to see what turns up…
 
See also A cellular basis for heightened gut sensitivity in females (2025, Science) —

We identified an estrogen-responsive paracrine pathway in which two enteroendocrine cell types, peptide YY (PYY)–expressing L cells and serotonergic EC cells, communicate to increase gut sensitivity in females. We demonstrate that estrogen signaling up-regulates the bacterial metabolite short-chain fatty acid receptor Olfr78 on colonic L cells, increasing PYY release and their sensitivity to acetate. Elevated PYY acts on neighboring EC cells by means of NPY1R, thereby enhancing serotonin release and gut pain.
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Here are a few more papers on extrinsic olfactory receptor Olfr78, grouped by system. (I haven't read these yet)

Respiratory / Hypoxia / Lactate

Oxygen regulation of breathing through an olfactory receptor activated by lactate (2015, Nature)
Animals have evolved homeostatic responses to changes in oxygen availability that act on different timescales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long-term responses to low oxygen (hypoxia) has been established1, the pathway that mediates acute responses to hypoxia in mammals is not well understood.

Here we show that the olfactory receptor gene Olfr78 is highly and selectively expressed in oxygen-sensitive glomus cells of the carotid body, a chemosensory organ at the carotid artery bifurcation that monitors blood oxygen and stimulates breathing within seconds when oxygen declines2. Olfr78 mutants fail to increase ventilation in hypoxia but respond normally to hypercapnia. Glomus cells are present in normal numbers and appear structurally intact, but hypoxia-induced carotid body activity is diminished.

Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation3,4,5,6, activates Olfr78 in heterologous expression experiments, induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78.

We propose that, in addition to its role in olfaction, Olfr78 acts as a hypoxia sensor in the breathing circuit by sensing lactate produced when oxygen levels decline.



The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages (2021, Proceedings of the National Academy of Sciences)
Expression and function of odorant receptors (ORs), which account for more than 50% of G protein–coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumor-derived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs).

In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage–tumor axis. Using Olfr78+/+ and Olfr78−/− bone marrow–derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population.

We propose that the Olfr78–lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.

SIGNIFICANCE
Expression and function of odorant receptors (ORs) are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Here, we hypothesized that the macrophage OR Olfr78 functions as a tumor-derived lactate sensor and shapes the macrophage–tumor axis. Olfr78 and the G protein–coupled receptor Gpr132 form a heterodimer that senses lactate in the tumor microenvironment, leading to generation of tumor-associated macrophages with a protumoral M2 phenotype, which promotes tumor progression and metastasis. Our findings suggest an alternative strategy for cancer treatment, namely targeting the interaction between tumor-derived metabolites and ORs.

Hypothalamus / Vascular / Fluid Balance

Olfactory receptor 78 is expressed in hypothalamic vasopressin/oxytocin neurons, parenchymal microglia and choroidal macrophages in mice (2022, Molecular Brain)
Olfactory receptors have been detected in extraolfactory organs. Olfactory receptor 78 (Olfr78), proposed to respond to small organic acids, is widely expressed in the kidney, arterioles, colon, and prostate. However, its expression patterns in the brain remain largely unknown.

Using immunohistochemistry, we revealed that Olfr78 was densely expressed in the hypothalamus and choroid plexus and sparsely expressed throughout the parenchyma. By costaining with cellular markers, we further found that Olfr78 was expressed in the somata and axons of vasopressin/oxytocin neurons in the hypothalamic paraventricular/supraoptic nuclei. Olfr78 was also strongly expressed in macrophages in the choroid plexus and moderately expressed in microglia near the parenchymal vasculature.

Considering that these brain regions should communicate with cerebral blood flow, Olfr78 could contribute to sensing the humoral conditions surrounding the cerebrovascular system.

Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation (2013, Proceedings of the National Academy of Sciences)
Olfactory receptors are G protein-coupled receptors that mediate olfactory chemosensation and serve as chemosensors in other tissues. We find that Olfr78, an olfactory receptor expressed in the kidney, responds to short chain fatty acids (SCFAs).

Olfr78 is expressed in the renal juxtaglomerular apparatus, where it mediates renin secretion in response to SCFAs. In addition, both Olfr78 and G protein-coupled receptor 41 (Gpr41), another SCFA receptor, are expressed in smooth muscle cells of small resistance vessels.

Propionate, a SCFA shown to induce vasodilation ex vivo, produces an acute hypotensive response in wild-type mice. This effect is differentially modulated by disruption of Olfr78 and Gpr41 expression. SCFAs are end products of fermentation by the gut microbiota and are absorbed into the circulation. Antibiotic treatment reduces the biomass of the gut microbiota and elevates blood pressure in Olfr78 knockout mice.

We conclude that SCFAs produced by the gut microbiota modulate blood pressure via Olfr78 and Gpr41.

Olfactory receptor 78 modulates renin but not baseline blood pressure (2021, Physiological Reports)
Olfactory receptor 78 (Olfr78) is a G protein-coupled receptor (GPCR) that is expressed in the juxtaglomerular apparatus (JGA) of the kidney as well as the peripheral vasculature, and is activated by gut microbial metabolites. We previously reported that Olfr78 plays a role in renin secretion in isolated glomeruli, and that Olfr78 knockout (KO) mice have lower plasma renin activity. We also noted that in anesthetized mice, Olfr78KO appeared to be hypotensive.

In this study, we used radiotelemetry to determine the role of Olfr78 in chronic blood pressure regulation. We found that the blood pressure of Olfr78KO mice is not significantly different than that of their WT counterparts at baseline, or on high- or low-salt diets. However, Olfr78KO mice have depressed heart rates on high-salt diets. We also report that Olfr78KO mice have lower renin protein levels associated with glomeruli. Finally, we developed a mouse where Olfr78 was selectively knocked out in the JGA, which phenocopied the lower renin association findings.

In sum, these experiments suggest that Olfr78 modulates renin, but does not play an active role in blood pressure regulation at baseline, and is more likely activated by high levels of short chain fatty acids or hypotensive events. This study provides important context to our knowledge of Olfr78 in BP regulation.

Olfactory receptor Olfr78 prostate-specific G protein-coupled receptor PSGR expression in arterioles supplying skeletal and cardiac muscles and in arterioles feeding some murine organs (2021, Histochemistry and Cell Biology)
The olfactory receptor Olfr78 (prostate-specific G protein-coupled receptor PSGR) is a member of the G protein-coupled receptor family mediating olfactory chemosensation, but it is additionally expressed in other tissues. Olfr78 expressed in kidney participates in blood pressure regulation, and in prostate it plays a role in the development of cancer.

We here screened many organs/tissues of transgenic mice co-expressing β-galactosidase with Olfr78. X-gal-positive cells were detectable in smooth muscle cells of numerous arterioles of striated muscles (heart ventricles and skeletal muscles of various embryological origin). In addition, in most organs where we found expression of Olfr78 mRNA, X-gal staining was restricted to smooth muscle cells of small blood vessels.

The dominant expression of Olfr78 in arteriolar smooth muscle cells supports the concept of an important role in blood pressure regulation and suggests a participation in the fine tuning of blood supply especially of striated muscles. This should be considered when targeting Olfr78 in other contexts such as prostate cancer.

Gut / Metabolism

Gut microbial short-chain fatty acids-mediated olfactory receptor 78 stimulation promotes anorexigenic gut hormone peptide YY secretion in mice (2021, Biochemical and Biophysical Research Communications)
Olfactory receptor 78 (Olfr78), which is also known as a receptor for short-chain fatty acids (SCFAs) produced via gut microbial fermentation from indigestible polysaccharides such as dietary fibers, is expressed in the enteroendocrine cells of the colon. However, the role of Olfr78 in gut hormone secretion remains unknown.

Here, we aimed to investigate the function and mechanism of action of Olfr78 in vivo and in vitro. Toward this, we assessed the expression of Olfr78 in several tissues, affinity of Olfr78 to various monocarboxylates, and the secretion of anorexigenic gut hormone peptide YY (PYY) via Olfr78 using various molecular and biochemical techniques.

Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line STC-1 and showed specific affinity to SCFAs such as acetate and propionate, but not butyrate, in a monocarboxylate ligand screening assay using a heterologous expression system. Acetate promoted PYY secretion in STC-1 cells via Olfr78-protein kinase A signaling, whereas the effects were abolished by Olfr78 RNA interference. Colonic SCFAs production via oral administration of fructo-oligosaccharide significantly increased plasma PYY levels, whereas this effect was abolished in Olfr78-deficient and germ-free mice.

These results suggested that the SCFA receptor Olfr78 is important for anti-obesity and anorexigenic effects of the gut microbiota and dietary fibers.

HIGHLIGHTS
• Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line.

• Olfr78 was activated by SCFAs, acetate and propionate, but not butyrate.

• Acetate mediated Olfr78 stimulation promoted PYY secretion in STC-1 cells.

• Gut microbial SCFAs increased plasma PYY levels via Olfr78.

Olfr78, a novel short-chain fatty acid receptor, regulates glucose homeostasis and gut GLP-1 secretion in mice (2023, Food Frontiers)
Olfr78, which is a novel receptor for short-chain fatty acid (SCFA) acetate and propionate, plays essential roles in some cellular processes. The present study aimed to investigate the role of olfr78 in regulating energy metabolism and delineate the underlying mechanisms using olfr78−/− mice.

Deletion of olfr78 did not influence the adiposity of mice fed either normal chow or a high-fat diet (HFD). However, olfr78−/− mice exhibited glucometabolic dysfunction, as evidenced by increased fasting blood glucose levels, decreased serum insulin levels, and impaired oral glucose tolerance under HFD feeding.

When compared to wild-type (WT) mice, olfr78 deficiency enhanced HFD-induced gluconeogenesis and increased the mRNA expression of key gluconeogenic genes in the liver and kidney. Quantitative real-time PCR results revealed that olfr78 expression was higher in the colon compared with other tissues in WT mice.

Analysis of the gut microbiota in the feces of olfr78−/− mice using 16S rRNA gene sequencing revealed altered relative abundances of some representative SCFAs producers along with decreased levels of SCFAs, including propionic, isobutyric, 2-methylbutyric, valeric, isovaleric, and 4-methylvaleric acids. Importantly, mice lacking olfr78 had low circulating levels of glucagon-like peptide 1 (GLP-1). In the STC-1 enteroendocrine cell line, propionate and acetate induced the secretion of the gut hormone GLP-1, and this effect was partially abolished by olfr78 siRNA-mediated knockdown.

Together, these results suggest a previously undescribed, specific regulatory role for gut olfr78 in glucose homeostasis and highlight olfr78 as a potential target for diabetes treatment.
 
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I saw this weird Negr1 olfactory paper yesterday when combing through NEGR1 papers:

pubmed.ncbi.nlm.nih.gov

NEGR1 Modulates Mouse Affective Discrimination by Regulating Adult Olfactory Neurogenesis - PubMed

NEGR1 contributes to mouse affective recognition, possibly by regulating olfactory neurogenesis and subsequent olfactory sensory processing. We propose a novel neurobiological mechanism of autism-related behaviors based on disrupted adult olfactory neurogenesis.
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

 
My feeling since digging into it is there’s signal in that PrecisionLife data. I can see potential stories, we just need someone able to tell what’s fairytales and what can be backed up.
 
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