Why are olfactory receptors activated? (2023)

INTRODUCTION

Olfactory receptors (ORs) detect volatile chemicals that are common odors in the environment. In 1991, Linda Buck and Richard Axel (21) discovered a large multigene family (~1400 members) encoding G protein-coupled receptor (GPCR) proteins in the mouse genome and postulated that ORs are expressed exclusively in the olfactory epithelium. Beginning with the first comprehensive study of ORs in the human genome (153), ~900 human OR genes have been identified, including ~400 OR genes that have an intact open reading frame (207). Interestingly, it took almost 7 years before the first successful deorphanization of an OR was achieved by recombinant expression of zebrafish OR in HEK293 human embryonic kidney cells (193) and in vivo adenovirus-mediated gene transfer of the OR. I7 cloned mice. Electrophysiological recordings showed that overexpression of this gene was sufficient to generate responses to C7-C10 aliphatic aldehydes (210). In parallel, the expression of hOR17-40 (OR3A1) in HEK293 cells together with G proteins provided the first evidence for an OR human odor interaction, olfactory examinations were performed and specific odors (helional and heliotropylacetone) were identified as binding, measuring transient elevations. of intracellular calcium levels using calcium imaging technology (198).

Despite the initial assumption that they were restricted to the olfactory epithelium (OE), 1 year after the discovery of the OR genes, Parmentier et al. (140) identified the first extranasal transcripts of the OR gene in mammalian germ cells. Over the next two decades, additional descriptive studies revealed ectopic expression of other OR genes in a variety of human tissues throughout the human body (1, 35a, 44, 47, 50, 89). In general, the term fallopian tube is defined as a biological event or process that occurs at an abnormal site or location within the body (44). However, the expression of ORs outside the OE occurs in a more unexpected place than in an abnormal place.

Although the sense of smell is not essential for human survival, its loss can indicate various neurodegenerative processes and significantly affect the quality of life of an affected person. This can also serve as a starting point for future studies trying to understand the underlying pathologies. However, several ORs appear to be highly conserved among mammals and are subject to stronger evolutionary constraints than OR genes expressed exclusively in the EO (35a).

In particular, some of the evolutionarily oldest fish-like ORs (OR51E1 and OR51E2) (51, 133) share ~94% sequence similarity to their mammalian orthologs (136, 154, 208); however, they are widely expressed and have different transcript and protein levels in various human tissues (47, 118, 180). This phenomenon underscores the importance of OPs conserved outside the OE and their potential to function beyond the sense of smell. Initially, a minor or even artificial role was predicted for human ORs detected at the transcriptional level (44). However, to date, the protein abundance and cellular function of increasing numbers of ORs have been elucidated. The first evidence for the role of an extranasally expressed OR was shown for human hOR17-4 (OR1D2) (173) and mouse MOR267-13 (ortholog of human OR10J5) (54) in sperm chemotaxis and chemokinesis. Several important physiological and pathophysiological processes have now been described as targets of human ORs, including pathfinding, cell growth, differentiation and apoptosis, migration, and secretion (4, 17, 24, 49, 60, 82 , 88, 115, 116, 118, 119132, 150, 158164, 173, 179182, 191, 209). Ectopic ROs may play a role that is not limited to humans but also to other mammals, mainly mice, which have been found to be involved in similar physiological processes (36, 54, 67, 144, 145, 166).

However, the function of most O.R.s on non-olfactory tissues remains unclear, as the odors that trigger them are currently unknown. This review article summarizes the appearance of human operating rooms outside the nose, focusing on its effects on various human tissues. Understanding the molecular and cellular mechanisms of action forms the basis for accepting the functional importance of extranasal spaces and suggests their clinical utility.

II Ectopically expressed human olfactory receptors

Since the first discovery of ectopically expressed ORs in mammalian testes (140), the number of studies aimed at detecting OR expression in non-olfactory tissues has steadily increased. Building on the rapid technical advances that have been made in the last two decades, comprehensive transcriptome analyzes have further facilitated the systematic exploration of numerous OR genes that are transcribed throughout the human body (35a, 44, 47, 77 ). Currently, detection of OR transcripts is largely based on relatively new (q)RT-PCR, microarray, or NGS (RNASeq) assays. These methods allowed a comparable and quantitative analysis of OR expression at the mRNA level. Transcriptome data is available for more than 45 different human tissues, including the cardiovascular, gastrointestinal and accessory organs of digestion, the nervous system, the musculoskeletal, reproductive, respiratory and urinary tracts, skin and blood. Within these tissues, each tissue type examined showed the expression of at least one OR (35a, 44, 47, 109, 180), as exemplarily demonstrated for 16 tissues in the Bodymap project (FIGURE 1). The expression pattern of ORs in a given tissue is relatively stable; However, the number of ORs expressed in different human tissues varies considerably, from a few ORs in liver or skeletal muscle to more than 60 ORs in testis(47). In general, OR genes generally have a lower average level of expression in non-olfactory tissues compared to human OE (135).

Several ORs show a broad tissue distribution, while other ORs appear to be exclusively tissue-specific (44,47). The most highly expressed OR, OR4N4 in human sperm, is an example of a highly and selectively expressed OR. Expression of this OR is virtually undetectable in other tissues, including human OS (49,135). However, despite the availability of a specific antibody, this receptor protein has not been detected in several sperm samples (49). Another specifically expressed receptor is OR6B3, which is highly expressed in the spinal ganglion (DRG), trigeminal ganglion (TG), and retina (48, 83).

In the case of another widespread candidate, OR2A7 (OR2A4, 99% sequence homology), parts of its open reading frame (ORF) overlap with an exon of Rho-guanine nucleotide exchange factor pseudogene 34 (ARHGEF34P). . However, OR2W3 and OR2A4/7 have been detected by immunostaining in various cell lines and tissues (49, 56, 118, 179, 209), indicating the ability of the transcript to produce OR proteins. These are practical examples showing that the ectopic expression of OR is subject to a highly variable and complex regulatory mechanism. It has been suggested that ectopic gene expression is a widespread phenomenon in multicellular organisms associated with regulatory leaks in gene expression. This process may have significant evolutionary importance because gene expression is flexible over a wide range of structural and functional diversity(151). This phenomenon is reinforced by the multifunctional properties of the same OU expressed in different human tissues (24,115,116,179). Expression of the ectopic OR gene does not depend on the genomic locus; However, highly expressed non-OR gene clusters harboring the coding sequences of ORs positively affect OR transcript levels (44), with the exception of the highly expressed ORs OR51E1 and OR51E2, which lack genes. highly expressed non-OR of neighboring genes (47). ) .

OR51E1 (PSGR2) and OR51E2 (PSGR) are examples of ORs that are expressed throughout the human body, although their frequency is substantially increased in prostate tissue, particularly in prostate cancer (35, 192). Furthermore, the expression of OR51E2 in prostate cancer tissue is even higher than in human EO (135) and comparable to highly expressed housekeeping genes in some individuals (118). However, most ORs have comparatively low expression levels when looking at the whole tissue transcriptome (47). Overall, it seems plausible that the relatively low levels of OR expression are due to the small number of cell types that are expressed within the more complex and heterogeneously organized tissue structures.

OR2W3, one of the most frequently expressed candidates, is abundant in at least 20 different human tissues (47, 83, 111, 147). However, detailed analyzes indicate divergent OR2W3 post-transcriptional splicing events in human tissues. In human brain, lung, thyroid, white blood cells, DRG, and presumably other tissues that have yet to be studied, the complete OR2W3 coding sequence is part of chimeric transcripts with the upstream E3-ubiquitin protein ligase gene encoding Trim 58 (47th, 48). The oncogenesis of several common cancers has been attributed to recurrent gene fusion (124, 176); therefore the functional relevance of OR2W3 remains an open but interesting question.

Previous reports of transcripts in the antisense orientation support the idea that OR transcripts may perform functions beyond encoding functional OR proteins (49). The functional role of antisense OR transcripts has not currently been explored; however, antisense transcription has been attributed to gene expression and regulation of chromatin modification (125, 141).

In contrast to the OR repertoire of a single OSN (72), more than one ectopically expressed human OR has been identified in the same cell type (49, 60, 83, 85, 114, 115, 119, 158, 179, 182 , 191). In murine OE, OR expression is monoallelic, with each ORN expressing only one allele of an OR gene (29, 31, 72). In mice, this choice of the OR gene depends on several principles, including the action of H elements (55, 108) or heterochromatic silencing by histone methyltransferases (110). In the case of ORs expressed ectopically outside the OE, the mechanisms regulating gene expression are markedly different. More than one OR is co-expressed in many characterized cell types, and mRNAs for multiple receptors may be present in single cells in testis and sperm (49). There are limited reports of the regulation of the OR gene outside of OE. A complex pattern of OR transcriptional variants has been observed in the testes (184). Here, six different transcription thresholds were found for one OR gene (hs6M1-16, also known as OR2H1). A common start site with potential bidirectional transcriptional activity has been identified for other ORs (hs6M1-18, -21, and -27, also known as OR11A1, OR5V1, and OR12D3) (184). A variety of alternative splicing events have been identified in the 5' untranslated regions of the gene (5'UTR), as well as the presence of different promoters for other ORs (47, 48, 135, 184). For example, the expression of the OR51E2 gene is controlled by different promoters in the OS and in the prostate (135).

Considering that ORs are found in most of the human body, they appear to be much more important from a functional point of view than previously thought. During the last decade, a growing number of studies have demonstrated its ability to act on physiological and pathophysiological cellular processes. This is mainly based on a growing number of deorphanized human ORs, so it should be noted that the identified ligands are often synthetic compounds and their physiologically relevant endogenous activating substances are still unknown. However, the cellular role of ORs can be studied using synthetic substances. However, there may be more potent natural ligands that can activate the receptor at much lower concentrations. The following section highlights the key findings.

third PHYSIOLOGICAL FUNCTIONS OF ECTOPICALLY EXPRESSED OLFACTORY RECEPTORS

At the transcriptional level, a plethora of ORs have been discovered in various human tissues (FIGURE 1); however, far fewer reports have been made on its protein occurrences. Few studies have demonstrated the functional effects on the cells or cell lines of the respective tissues (FIGURE 2). Evidence has rapidly accumulated that ORs are involved in important cellular processes outside of their primary sensory organ, where they function in odor recognition and discrimination (Table 1).

Tabla 1.Physiological functions of ectopically expressed ORs

A. Cardiovascular system

The functional analysis of ectopic ORs in the cardiovascular system is of particular interest as they have enormous potential to act as the main carriers of endogenous and exogenous odorants throughout the human body.

OR10J5 is expressed in human aortic, coronary artery, and umbilical vein endothelial cells (HUVECs). Its activating odorant, Lyral, induces intracellular Ca2+ entry and protein kinase B (AKT) phosphorylation, leading to increased migration and angiogenesis (93).

Another function has been proposed for the human heart: the "engine" of blood circulation. In this study, next-generation sequence analysis revealed the expression pattern of approximately 10 different ORs in adult and fetal human cardiomyocytes and identified the fatty acid-sensitive OR51E1 as the most expressed OR at both stages of cardiac development. Nonanoic acid and structurally related medium chain fatty acids have been identified as potent agonists, and 2-ethylhexanoic acid has been identified as a receptor antagonist. Several agonists have been identified at receptor-activating concentrations in plasma and epicardial adipose tissue, particularly in diabetic patients. Administration of OR51E1 agonists induced negative chronotropic (reduced heart rate) and inotropic (reduced contractile force) effects in cardiac trabeculae and sections of explanted human ventricles and human stem cell-derived cardiomyocytes. The effect was reversed in the presence of the antagonist, suggesting a possible clinical use. These findings suggest that OR51E1 may play a role as a metabolic regulator of cardiac function (82).

B. RO in the cellular immune system

OR transcripts have been identified in a variety of human blood cells, e.g. B. erythrocytes, peripheral blood mononuclear cells (PBMC), natural killer cells, B and T cells, and polymorphonuclear neutrophils (11, 43, 47, 114, 117, 211). . Butter-flavored compounds, known ligands for a variety of class I ORs expressed in various blood cell types (114), induce chemotactic behavior in human neutrophils (57). Odorants also act on immune cells of the murine immune system, where they can inhibit chemokine-driven chemotaxis in CD4+ T cells (30) or regulate macrophage function (104).

Additionally, OR function has been associated with myeloid leukemia. Sandalore-dependent activation of OR2AT4 leads to decreased proliferation and increased apoptosis of acute myeloid leukemia cells through increased cell cycle arrest at G0/1 and G2/M phases (115). Furthermore, in the presence of an agonist, growth inhibition is accompanied by increased numbers of hemoglobin-bearing erythroid cells derived from immature precursor myeloblasts. Inhibition of myeloid leukemia cell proliferation is also mediated by another OR, OR51B5 activated by isoyl alcohol (116). Both receptors initiate diverse and complex signaling pathways, including activation of intracellular Ca2+ transients and activation of other downstream effectors, e.g. B. Kinases. This discovery offers new opportunities for the development of therapeutic approaches to treat acute myeloid leukemia.

C. Gastrointestinal system and additional digestive organs

The identification of ectopic ORs in the human gastrointestinal (GI) system and accessory digestive organs is an intriguing discovery given the accessibility of external stimuli from the environment, such as food intake. In addition, there are odorous chemicals that are also produced internally by the microbiome (145). In enterochromaffin (EC) GI cells, known OR ligands cause an increase in intracellular Ca2+, leading to increased release of serotonin (17, 92), an important regulator of peristalsis and intestinal secretion. Therefore, operating rooms can significantly contribute to abnormal bowel functions, such as diarrhea or constipation. Detection via OR has been demonstrated in other regions along the human gastrointestinal tract. In addition to its potential role as a tissue biomarker in neuroendocrine carcinomas of the small intestine(34), activation of the newly identified and deorphaned OR51B4 affects the cellular physiology of colorectal cancer. The troenan agonist causes inhibition of cell proliferation and migration, which is accompanied by pro-apoptotic properties (191). The negative effect on cell growth was initiated by a phospholipase C (PLC)-dependent signaling pathway, including Ca2+ entry via calcium release-activated channels (CRACs), increased protein kinase phosphorylation mitogen-activated p38 (MAPK) and decreased mTor and Akt-kinase phosphorylation. It can be assumed that these findings will contribute to future new concepts for colorectal cancer therapies. Since colon tumors are often accessible from the lumen, oral or rectal application of troenan in effective concentrations is conceivable (191).

The liver harbors a smaller number of ORs compared to the GI and other tissues (47); however, the two paralog-related receptors OR1A1 and OR1A2 have been shown to play important roles in hepatocyte physiology (119,203). In general, the liver plays a central role in metabolic processes; It is responsible for detoxifying substances that enter the bloodstream and providing bile for digestion. Therefore, the liver is in close contact with the external environment. OR1A1 activation by the terpene (-)-carvone leads to reduced expression of the mitochondrial glycerol-3-phosphate acyltransferase (GPAM) gene involved in triglyceride synthesis (203), suggesting that the Receptor might be involved in liver metabolism. In hepatocellular carcinoma cells, activation of OR1A2 by (-)-citronellal results in decreased proliferation through initiation of a cAMP-dependent signaling pathway similar to that of OSNs and phosphorylation of p38 MAPK (119 ). These results are consistent with several studies that have described the anticancer properties of terpenes (66, 76), suggesting that terpene-activated ORs represent promising targets for the development of anticancer therapies.

Recently, a functionally important OR has been identified in the human pancreas. In pancreatic EC cells, the helium-activated OR2J3 has been shown to be involved in serotonin secretion, similar to the ORs in EC cells present in the human GI. In contrast, OR2J3 activation causes a cGMP-dependent protein kinase-mediated decrease in intracellular Ca2+.(package) (86). In addition to its role as a neurotransmitter in the central nervous system, serotonin plays a variety of roles in non-neuronal tissues. In the pancreas, its molecular targets are intracellular GTPases. Serotonin is covalently linked to these enzymes by a transglutaminase. This protein serotonin further regulates insulin secretion, and a lack of serotonin causes signs of diabetes (149). In summary, OR-mediated regulation of Ca2+ homeostasis has a significant impact on the functional units of the gastrointestinal tract.

The identification of ectopically expressed members of the TASR1 and TASR2 families of sweet, umami, or bitter taste receptors highlights another class of chemoreceptors that is expressed in addition to ORs in the GI tract (25, 37, 103). These receptors serve as chemical sensors, analyzing, for example, the luminal contents of the intestine and regulating a variety of physiological functions, such as energy and glucose homeostasis, the release of intestinal hormones and neurotransmitters (37). These receptors are present on enterochromaffin and brush cells(157) and, therefore, can be co-expressed with ORs present on enterochromaffin cells of the gastrointestinal tract(17). Co-expression of these different receptor types with OR can significantly increase the number of chemical signals detected, since each receptor family is restricted to a subclass of ligands.

D. Genito-Harn system

After the initial discovery of ectopic expression of OR in the testes (140), efforts to determine its location and physiologic function increased significantly. Sperm have been shown to have distinct chemosensory capabilities that allow for chemical communication during fertilization of the egg. Recently, the complete testicular and spermatic OR transcriptional repertoire has been demonstrated, highlighting the testis as the richest OR transcriptional expression tissue outside the nose (47,49). Various functions of ORs have been suggested based on their different protein positions in human sperm (49). Located in the midpiece (130), OR1D2 (OR17-4) was the first ectopic OR identified. Activation by its civic synthetic agonist results in faster swimming speed and increased flagellar beat frequency, demonstrating a functional role in sperm chemotaxis (173). The involvement of OR1D2 in the regulation of swimming behavior and speed has been confirmed using its specific undechannel antagonist (173). Recently, reduced sensitivity of olfactory perception to Bourgeois has been correlated with idiopathic infertility (137, 170). OR1D2 activation initiates the translocation of cytosolic β-arrestin2 to the nucleus, which may result in the regulated gene expression required for fertilization or early embryogenesis (130). Activation of additional ORs, OR7A5 and OR4D1, has been shown to affect sperm motility by Myrac and PI-23472 odors, respectively (182). It has also been shown that different ORs are expressed in the same sperm, although predominantly in different compartments, using specific antibodies and antagonists for the different ORs (49,182). Interestingly, analysis for the presence of odorous compounds in vaginal secretions and follicular fluid by gas chromatography-olfactometry revealed about 20 different odorants, including well-established activators of OR1D2. The other ligand candidates for OR were further tested for induction of Ca2+ signaling in sperm. Using this approach, two new odorant-ligand-receptor pairs have been reported (5α-androst-16-en-3-one for OR4D1 and 4-hydroxy-2,5-dimethyl-3[2H]-furanone for OR7A5). than induce higher levels of Ca2+ in human sperm in response to both natural odorants (74). Most of the ORs are functionally characterized in sperm-induced Ca2+ transients (7 of 10) after stimulation with their activating odors (49, 173, 182), although not all OR activation signals cause an increase in Ca2+. There may also be Ca2+-independent signaling components that have not been tested. In sperm, odors do not activate the canonical signal transduction cascade and instead act independently to activate adenylyl cyclase and second messenger cAMP (18,182). In addition, several odorants, including Bourgeois, can also act directly on the CatSper calcium channel in human sperm (18), and odor-induced Ca2+ signaling requires a calcium-permeable channel and extracellular calcium. Mibefradil, which inhibits a variety of calcium channels in sperm, including CatSper (14, 41, 175, 197), also blocks odor-induced Ca2+ signaling (49). In conclusion, the exact mechanism underlying how odors induce Ca2+ signaling in sperm and the role of ORs and CatSper channels in particular need to be further investigated.

As part of the urinary system, the human kidney also harbors functionally active ORs. The structurally related agonists of OR51E1 and OR11H7 induce intracellular Ca2+ flux in renal proximal tubular cells through adenylyl cyclase (AC) activity (87). The murine ortholog of OR51E2, the OR51E1 paralog, has been shown to mediate renin secretion after short-chain fatty acid (SCFA) stimulation in the murine kidney and affect blood pressure regulation (144,164). These data support the potential for human operating rooms to interfere with the physiological processes of the kidney.

Another function of ORs has been proposed for the human prostate. The generalized OR51E1 and OR51E2 receptors were originally thought to be GPCRs that were highly restricted to prostate tissue and were therefore mistakenly named prostate-specific G-protein-coupled receptors (PSGR1/PSGR2). To date, both ORs have been found to be ubiquitously expressed in various human tissues (47), albeit at significantly lower levels. OR51E2 was originally identified as the first hormone-activated membrane-bound rhodopsin-like GPCR. Activation by its agonist β-ionone, a synthetic terpenoid, and the steroid hormone 1,4,6-androstatriene-3,17-dione (ADT) leads to reduced proliferation of prostate cancer epithelial cells (PCa) in vitro and in LNCaP-Cells (132). The apoptotic effect exerted by β-ionone, accompanied by initiation of prostate cancer cell cycle arrest, has been demonstrated in subsequent studies (81), supporting the idea that OR51E2 may also function as a key mediator in these processes. Activation of OR51E2 leads to inhibition of the growth of androgen-dependent and castration-resistant prostate cancer cells (26, 132); however, β-ionone stimulation increases cell invasion (26,158).

OR51E1 activation has also been suggested to affect the growth of prostate cancer cells. Stimulation with nonanoic acid and decanoic acid, which specifically activate OR51E1 (82,155), significantly reduced proliferation and induced cell senescence in the LNCaP prostate cancer cell line in vitro (118). In addition, this receptor appears to interfere with androgen receptor (AR)-mediated signaling due to reduced levels of prostate-specific antigen (PSA), the androgen-regulated target gene, and the prostate homeobox protein, which the tumor suppressor gene encodes. NKX3. -1(118). This has led to the assumption that OR51E1 contributes significantly to the pathogenesis and progression of prostate cancer (PCa).

In cervical cancer (HeLa) cells, OR1A2 and OR2A4 have been shown to participate in cytokinesis. SiRNA-mediated knockdown of both receptors resulted in incomplete cell separation (209). Furthermore, knockdown of OR2A4 and OR1A2 promoted cytokinesis failure at early and late stages, respectively. Therefore, both receptors represent promising targets for the development of therapeutic strategies. The diverse physiological and pathophysiological roles of ectopic ORs underscore their important features in the human urogenital system.

E. Nervous system

Besides the association of RO and neuropathological diseases, there is only limited knowledge about its odor-induced influence on physiological or pathophysiological processes in neuronal systems. However, it has been suggested that ORs assume functions in the central nervous system. Activation of overexpressed human OR4M1 in primary mouse corticohippocampal neurons by acetophenone results in decreased phosphorylation of abnormal microtubule-associated tau protein and decreased c-Jun NH2-terminal kinase activity via a pathway cAMP-dependent (JNK) (211). This phenomenon leads to the assumption that OR4M1 might disrupt aberrant tau hyperphosphorylation involved in the pathogenesis of neurodegenerative diseases. These assumptions were confirmed by findings documenting dysregulation of olfactory receptors in the brain of patients with neurodegenerative diseases (7). In the human nervous system, the orphan OR OR6B3 was found to be highly selectively expressed in the trigeminal and spinal ganglia. Their activating ligands and their function are unknown (48). The new data describe the first assessment of OR mRNA expression and the unambiguous localization of OR proteins in the human retina. Transcriptome analysis revealed an average of 14 OR transcripts in the neural retina; of these, OR6B3 was the most highly expressed OR. Immunohistochemical staining of retinal sections showed that OR2W3 localized to the light-sensitive membranes of the outer cone segment, while OR6B3 was identified in multiple cell types. OR5P3 and OR10AD1 were detected at the base of the cilium-connecting photoreceptor, and OR10AD1 was localized to the nuclear envelope of all retinal nuclei. The cell type-specific expression of ORs in the retina suggests that there are unique biological functions for these receptors(83).

F. Respiratory system

Like the gastrointestinal tract and the cardiovascular system, the respiratory system is in constant contact with the environment and therefore with volatile substances when they are inhaled. Different functional relevance of ectopic ORs in the human lung has been reported. In lung NEC cells, OR activation has been shown to affect serotonin release. In this case, however, olfactory stimulation caused a decrease in serotonin levels (69, 70). Amilbutyrate and the agonists OR2AG1 and OR1D2, respectively, affect the contractility of human airway smooth muscle cells (HASMC) (85). Amylbutyrate inhibited histamine-induced cell contraction, while Bourgeois increased HASMC contractility. Both processes are mediated by a cAMP-dependent increase in intracellular Ca2+ (85). Therefore, ORs could potentially be used as new therapeutic targets for asthma and other chronic inflammatory lung diseases in the future.

Non-small cell lung cancer (NSCLC) has a high prevalence and mortality rate and is difficult to treat. NSCLC cells are virtually resistant to current chemotherapy approaches, and surgical resection offers the only cure for most patients. OR2J3 expression was detected in the NSCLC A549 cell line. The helical agonist OR2J3 triggers intracellular Ca2+ release and ERK phosphorylation through phosphatidylinositol-3-kinase (PI3K) signaling. This induces apoptosis and inhibits cell proliferation and migration in long-term stimulation experiments(88). This study provided the first evidence for the functional expression of an OR in NSCLC cells and for its putative therapeutic effect.

G first

The skin is the outer barrier of the human body. Therefore, it is in constant contact with the environment and exposed to numerous external factors of chemical origin. Expression of a variety of cutaneous chemosensitive receptors facilitates the processing of these environmental stimuli by the skin. Several ORs have been identified in different cell types of the epidermal layer of human skin and cutaneous tissue (24, 44, 60, 179). In contrast to myeloid leukemia cells, the OR2AT4 receptor activated by Sandalore promotes the proliferation and migration of human keratinocytes, resulting in accelerated healing of skin wounds in an ex vivo system (24). Furthermore, Sandalore induced pannexin-mediated cell-cell communication between keratinocytes and trigeminal neurons via ATP in a coculture system (171), demonstrating that OR2AT4 may play a chemosensory role as a crucial mediator between environmental and the sensory system. It has been suggested that the additional ORs are involved in the processes of keratinocyte growth and migration. Similar to its effect on HeLa cells, OR2A4/7 is involved in keratinocyte cytokinesis (179). In addition, receptor activation by cyclohexyl salicylate increases cell proliferation and interleukin (IL)-1 production. In turn, isonyl alcohol-dependent activation of OR51B5 increases keratinocyte migration and regeneration, accompanied by IL-6 secretion (179). Recent studies have shown that OR51E2 also acts in the homeostasis of human melanocytes (60). Melanocytes are the pigment-containing cells of the epidermis that protect the skin from excessive sun exposure. The results of this study showed that β-ionone activation of OR51E2 leads to increased melanogenesis and dendritogenesis, as well as reduced cell proliferation (60). In primary cell cultures of melanoma cells of the metastatic and upright growth phases, β-ion-dependent activation of OR51E2 resulted in inhibition of cell proliferation and migration. These results are useful for understanding the involvement of OR51E2 in pathological disorders of pigmentation and cancer progression. They may also indicate new therapeutic directions for the treatment of melanoma (59).

4. ARE THE EXPRESSION PATTERNS OF OLFACTORY RECEPTORS LINKED TO DISEASE: BIOMARKERS OF POTENTIAL USE?

The relationship between OR expression levels and pathological changes is one of the most pressing questions to be addressed, as it provides the basis for identifying early and valuable disease biomarkers for diagnostic approaches. Several studies have shown that differentially expressed ORs are associated with pathological changes, predominantly in cancer and neuropathological diseases. The human prostate was the oldest and best studied tissue in terms of differential OR expression analysis. In addition to a low incidence in benign and healthy prostate tissue, the expression levels of OR51E1 and OR51E2 transcripts are elevated in high-grade intraepithelial neoplasia (HIG) and PCa, and their frequency has been suggested to be consistent with the pathological stage and the grade of the tumor. 52,192, 195, 196,206). Therefore, it has been suggested that both receptors represent useful PCa clinical biomarkers. The protein expression of both receptors was also evaluated in most of the samples of advanced PCa and expanding metastases studied (26, 118). These studies suggested that both operating rooms have diagnostic potential not only for early detection but also for tumor classification and progression and identification of metastases. In addition, the expression of OR51E2 and/or OR51E1 has been associated with the PCa biomarker alpha-methylacyl-CoA racemase (AMACR) and higher preoperative PSA levels (189, 206). The presence of OR51E2 in human urinary sediment facilitates its accessibility and increases the potential for using this receptor in "liquid biopsy" assays as a urinary PCa tumor marker (148). In addition, the novel chimeric fusion of PSGR with the erythroblast transformation (ETS)-specific transcription factor ETV1 has been identified as being involved in prostate carcinogenesis, which retains one of the active regulatory promoters OR51E2 (12, 194). Together, these studies reinforce the functional importance of OR51E1 and OR51E2 in the benign and malignant physiology of prostate tissue. However, a smaller number of PCa samples examined showed an inconsistent transcriptional expression pattern as well as strong interindividual variations (65, 118, 205), raising questions about its reliability as a single tumor marker. Other studies suggest that the expression of the OR51E2 protein is negatively associated with advanced PCa and decreases from PIN to advanced PCa (26), suggesting that its mRNA expression level in this case does not appear to be a predictor of the total amount of PCa. protein. Giandomenico and colleagues (34, 62, 102) later postulated that OR51E1 is a tissue biomarker for neuroendocrine carcinoma of the small intestine (SI-NEC) and somatostatin receptor-negative lung carcinoids. Using microarray analysis and qRT-PCR, this OR showed increased expression compared to normal tissues and the adjacent tumor microenvironment. Increased expression of multiple ORs has also been associated with CHEK2 1100delC breast tumors, as well as increased risk of salivary gland carcinoma (127,204). Another strategy was developed that could allow the systematic selection of tumor cells expressing OR51E2. This study reported on OR51E2-derived peptides that act as tumor-associated antigens recognized by CD8+ T cells(121). This may be of particular interest for the expression of OR51E2 in melanoma cells, which has recently been shown to be quite high (59).

OR7C1 plays a crucial role in the physiology of cells that initiate colon cancer. OR7C1 expression is correlated with increased tumorigenicity. OR7C1 overexpression in a SW480 CRC model led to an increase in cancer-initiating cells in nude mice. In addition to being a potential biomarker, OR7C1 is also a promising target of cancer-initiating cell (CIC) immunotherapy, with evidence suggesting that immunotherapy targeting only CIC via CIC antigen-specific cytotoxic T lymphocytes (CTL) is more successful than targeting all cancer cells. using common antigens (126).

Dysregulated expression of the OR gene has been associated with various neurodegenerative and neuropsychiatric disorders and has been studied in recent research (45). In the cortical regions of the brain and the substantia nigra of Parkinson's disease (PD) patients, several ORs (OR2L13, OR1E1, OR2J3, OR52L1, and OR11H1) have been found to be downregulated in the early stages of pathogenesis. of PD, demonstrating that its important role could support the course of the disease (56,68). Differentially regulated OR gene expression has also been identified in patients with Alzheimer's disease (AD), Creutzfeldt-Jakob disease, and progressive supranuclear palsy (7). In AD patients, half of the ORs found in cortical regions showed altered gene expression. OR11H1 appears to be upregulated, whereas the expression levels of OR4F4, OR10G8, and OR52L1 are reduced (7) and correlate with disease progression. In addition, the negative regulation of an OR associated with chronic schizophrenia was verified by the same group(8). The mechanism controlling the dysregulation of OR gene expression and OR function remains elusive. Therefore, this issue needs to be clarified in detail. In addition to their localization to brain regions, downregulated ORs in PBMCs have been implicated in traumatic brain injury (211). Dual detection of OR4M1 and OR11H1 is supposed to have diagnostic potential for biomarker analysis.

It has been suggested that specific mutations in the OR2W3 gene are associated with the eye disease retinitis pigmentosa (111). However, two reviews based on whole exome sequencing refuted the claim that the rare OR2W3 variant causes this autosomal dominant retinal disease (163, 208a). Recent studies have shown that OR2W3 does not form fusion transcripts with Trim58 and that the protein localizes specifically to the light-sensitive membranes of the outer cone segment (83), indicating possible cytophysiological roles in the human retina. In addition to its predominant role in disease, a common null variant in the OR1B1 gene has been associated with decreased serum cholinesterase activity, suggesting a potential impact on liver cell metabolism (97).

V. TRANSMISSION PATHWAYS OF SIGNALS INITIATED BY ECTOPICALLY EXPRESSED ORs AND THEIR MODULATION

Chemical signal processing upon activation of ectopically expressed ORs relies on a complex interplay of multiple signaling molecules, highly dependent on the OR involved and the cellular system (TABLE 1, FIGURE 3). The functional versatility of ORs is related to their considerable plasticity to activate various molecular and cellular mechanisms. For odor recognition, ORs trigger distinct signaling pathways in olfactory neurons that lead to the generation of electrical signals. According to current knowledge, ORs expressed in somatic cells do not generate action potentials in the same way as they do in olfactory neurons. In non-olfactory tissues, ORs can activate multiple signaling pathways. The specific pathway depends on the cell phenotype in terms of expression of signaling components. The most important critical component is probably the nature of the heterotrimeric G protein involved.

The gulf protein is widely expressed in peripheral human tissues (24, 47, 48, 85, 119). However, up to now there is no information on its effective functional involvement. In cardiomyocytes and prostate cancer cells, Gβγ has been proposed as an alternatively active subunit (82,158). In addition, there are limited data on Gq activation in enterochromaffin and colorectal cancer cells (17, 191). In addition to the poor knowledge of the G protein involved, several studies have demonstrated the presence and functional involvement of adenylyl cyclase and/or intracellular elevations of the second messenger cAMP in skin cells (24, 60, 179), hepatocytes (119, 203) . , blood cells (115, 116), enterochromaffin cells (86), kidney cells (145), and many other human tissues (47, 85, 174). The partial involvement of cAMP in ectopic OR signaling supports the hypothesis that at least one stimulatory G protein (Gαs) (24, 85, 119) is highly expressed throughout the human body (47). Interestingly, a specific alternative signaling pathway is present in Olfr73-expressing OSNs in mice. Methyl isoeugenol (MIEG), a weak Olfr73 agonist, triggers a signaling cascade independent of the canonical cAMP pathway leading to cellular depolarization. This pathway is mediated by Gαo activation, and this newly identified pathway coexists with the canonical cAMP olfactory pathway in the same OSN and is triggered by the same OR in a ligand-selective manner (162).

Activation of most ectopic ORs further leads to cAMP-induced calcium flux from outside the cells, a cascade reminiscent of the canonical pathway in OSNs (24, 47, 60, 85, 115, 116, 119 , 174, 179). Expression of the necessary subunits that make up the canonical heterotetrameric CNG channel (CNGA2, CNGA4, and CNGB1), particularly CNGA2, has not been detected in most human tissues (47). However, the native rod protein CNGA1 is capable of forming functional homomeric channels (90) and is activated primarily by cGMP in addition to cAMP (181). CNGA1 is the most prominent channel in peripheral cells and tissues (47) and is therefore probably capable of functioning as a potential CNG channel (24, 119). This channel, along with the CatSper channel, may be involved in OR-mediated sperm chemotaxis through Ca2+ control. Interestingly, a decrease in intracellular Ca2+ levels was observed by helionically activated OR2J3 in PKG-activated ochromaffin cells of the pancreatic center (QGP-1), since PKG-specific pharmacological inhibition with Rp-8-pCPT-cGMPS increases Ca2+ helionically induced. -Answer collected (86). . In addition, other results from pharmacological studies suggest that an OR-dependent increase in intracellular Ca2+ via PLC and inositol triphosphate (IP3) receptor-dependent depletion of internal Ca2+ stores in colorectal cancer cells (191) or the Ca2+ channel activation can be induced in enterochromaffin cells (17,86). In general, the nature of the Ca2+ channel through which Ca2+ enters remains unknown in most cases. Using more or less specific blockers, other studies have provided evidence for the involvement of sperm-specific TRP channels, CRAC channels, voltage-gated L-type Ca2+ channels, or sperm-specific CatSper channels (24, 49, 60, 86, 115, 116, 119, 191). In melanocytes, Ca2+ signaling triggered by OR51E2 consists of the release of Ca2+ from intracellular stores and an additive influx of Ca2+ from the extracellular space. Using specific channel blockers (2-APB) it was possible to identify members of the TRPM family that mediate the observed Ca2+ entry. The Ca2+ signal induced by β-ionone was significantly reduced (60). The paradigm that ectopic operating rooms exclusively initiate the canonical pathway was later refuted for individual cases. For example, the well-studied OR51E2 activated by β-ionone induces a pathway in prostate cancer cells that is quite different from the pathway in OSNs. This mode of signaling involves activation of the Src (sarcoma) tyrosine kinase, independent of an activated G protein, and an increase in intracellular Ca2+ mediated by the transient receptor potential V6 (TRPV6) channel in vitro (172). β-Ionone induces downstream phosphorylation of p38 MAPK and JNK/SAPK tyrosine kinase 2 (PYK2), which in turn inhibits downstream-regulated N-myc tumor suppressor gene 1 (NDRG1) (132,172,200). In addition, in advanced castration-resistant prostate cancer cells, β-ionone reduces phosphorylation of ribosomal protein kinase S6 (p70S6K) (26). At lower concentrations of β-ionone, it has been suggested that Gβγ-mediated signaling and downstream PI3K/AKT signaling are induced, which may mediate various physiological processes in vitro and in vivo (150,158). The paralog OR51E1 receptor, which is also expressed in prostate cancer cells, has been shown to disrupt AR-mediated signaling through Src kinase and several downstream kinases without inducing elevated intracellular Ca2+ and cAMP levels (118). The absence of intracellular Ca2+ signaling but an increase in cAMP levels and CREB phosphorylation for OR1A1 in hepatocytes after odor stimulation has also been identified (203). This, in turn, leads to expression of the Hairy and Division Enhancer 1 (HES1) gene and repression of peroxisome proliferator-activated receptor-γ (PPAR-γ), which is involved in triglyceride synthesis (203). .

Modulation of several downstream protein kinases after ectopic OR activation, mainly MAPK, has been identified in various cellular systems, whether initiating a canonical or alternative pathway (24, 26, 60, 93, 115, 116, 118, 150, 158, 179, 191, 200, 203). These protein kinases appear to be the most important downstream regulators of various physiological and pathophysiological processes. In summary, there are several mechanisms by which ORs mediate intracellular signaling after odor stimulation (FIGURE 3). In addition to the ORs and cellular systems involved, these processes are highly dependent on the structure and concentration of the odorant, the type or subunit of the heterotrimeric G protein, and the involvement of other less modulatory active proteins/cofactors, as well as the properties molecules of the cellular system.

SEEN. AGONISTS OF THE ECTOPICALLY EXPRESSED HUMAN OLACTORY RECEPTOR

It is now generally accepted that humans can distinguish around 10,000 different odors. However, a recently published study suggested that there may be up to a trillion different odors that can be distinguished by combinatorial activation of different ORs(23). However, the authors postulated this conclusion after making only 260 comparisons of 2 odors, of which only half could be distinguished. Reanalysis of the experiments by another group yielded controversial data that defended flaws in mathematical logic(123). However, at the molecular level, only ~10% of ~400 intact human ORs have been deparaffinized (3.24, 49, 53.58, 64, 75.79, 91, 105,112, 113, 120,132, 134, 155,159, 161, 168,173, 178, 179, 182, 191, 198). Due to the potential for exogenous chemicals to activate ectopically expressed ORs, it will be interesting to elucidate how tissue accessibility is ensured. Furthermore, the question arises whether endogenous components can be recognized by ORs expressed in certain tissues.

Many natural odorants that can activate ORs are found in plant essential oils, which can enter our bodies through the skin (80) and lungs (42, 183) or ingested with our daily diet. Essential oils are mainly composed of volatile terpenes and terpenoids, as well as aroma molecules (143). Several of these volatiles have been shown to activate ectopically expressed ORs and thus affect physiological processes in various human cells; Some examples include β-ionone (roses and berries), citronellal (citrus species), citronellol (pelargonium), thymol (thyme), and geraniol (rose oil and citronella oil) (3, 17, 70, 112, 119, 132, 155, 159). 161, 203, 211). The functional unit of terpenes, isoprene, is synthesized via the mevalonate pathway during cholesterol biosynthesis in animals (40, 63). Several metabolic intermediates of the mevalonate pathway share structural similarities with terpenes or terpenoids that activate OR, e.g. B. farnesol and geranylgeraniol (40). Other terpenes, eg thymol, etc.D-Limonene (linalool and linalyl acetate) and its metabolites have been detected in plasma within minutes after dermal or oral administration, sometimes in micromolar concentrations, and show a half-life of up to 12-24 h in mammals before being excreted in the urine, which means that the terpenes have a high bioavailability (19, 20, 78, 94-96, 183). As a result of the lipophilic nature of terpenes, a significantly higher affinity for lipid-rich tissues has been identified (33).

Another large group of exogenous and endogenous OR activators belongs to fatty acids, particularly short and medium chain fatty acids (SCFA/MCFA). Propionic acid-SFCA and its conjugate base, propionate, have been shown to activate recombinant and endogenous human OR51E2, respectively (144, 146, 155). Interestingly, propionic acid is produced endogenously by fermentation in mammalian gut microbiota at levels sufficient to activate OR51E2 (128, 145, 152, 155).

The paralog OR51E1 receptor is also activated by SCFAs, but is more sensitive to MCFAs with chain lengths from 5 to 14 carbons, such as the more potent nonanoic and decanoic acids, and valeric acid derivatives (53, 82, 118, 155). Isovaleric acid has also been shown to activate OR11H7 in human kidney cells (87). Free MCFAs that activate OR51E1 have been identified in human plasma and epicardial adipose tissue (32, 82). Therefore, it is likely that MCFAs not only originate from food intake, but are also released from adipose tissue. These findings provide the first evidence of a role for ORs in the regulation of cardiac functions through circulating natural ligands released into the plasma from epicardial adipose tissue.

Previously identified human sperm chemoattractants and the bourgeois OR agonists Myrac and PI-23472 (OR1D2, OR4D1, and OR7A5) are of synthetic origin (173,182). Interestingly, endogenous odors have also been identified in the female reproductive system. The compounds {5α-androst-16-en-3-one (androstenone) and 4-hydroxy-2,5-dimethyl-3[2H]-furanone}, which are endogenous agonists, were extracted from follicular fluid and vaginal secretion. using gas chromatography-olfactometry of OR activation and are able to induce Ca2+ transients in sperm (74). In addition, 5α-androst-16-en-3-one is present in human breast milk, urine, and axillary sweat (9,73) and has been shown to activate OR7D4 (91), which is expressed in the testes. and the epithelium ( 109, 135).

VII FUNCTIONAL CHARACTERIZATION OF HUMAN ODOR RECEPTORS: A GREAT CHALLENGE

After the publication of a comprehensive study(44) demonstrating the broad expression of OR transcripts in many human tissues, an intense debate began on the functional role of ectopically expressed ORs. In this study, a neutral or near-neutral evolutionary model of OR transcriptional control was discussed, "functionality being less likely" (44). However, the data do not exclude the possibility that a subset of ORs play functional roles in different tissues. By comparing OR expression levels in non-olfactory tissues in humans and chimpanzees, it was also shown that a subset of orthologous OR genes with conserved ectopic expression evolved under greater evolutionary pressure than OR genes exclusively expressed in OSNs (35a). These findings do not provide direct functional data, but further support the hypothesis that at least a subpopulation of OR genes have functions in non-olfactory tissues. In recent decades, several experimental projects have been developed to directly study the effects of OR activation in primary cell cultures or cell lines derived from non-olfactory tissues.

Therefore, knowledge of OR-dependent physiological (pathological) cellular functions has continuously increased. Despite the widespread use of tissue expression, the functions in human tissues have only been deciphered for a small number of ORs. A major obstacle to discovering its physiological function is the limited knowledge of its activating agonists. The deorphanization of the molecular receptive field of an SO is a prerequisite for its functional characterization. One problem that limits the identification of agonists is the relatively few composite mixtures of fragrances that exist, far from reflecting the chemical diversity of natural fragrance molecules. In addition, various odorants that activate OR can, in turn, act as antagonists to other ORs (169,173). This is accompanied by the discovery that some ORs exhibit high olfactory selectivity and respond only to structurally related odors, whereas other ORs are more widely attuned (46,155,177), allowing for high variability in olfactory encoding. Therefore, these findings indicate that the identification of novel receptor agonists is an immense challenge. Furthermore, the composition of odor mixtures is subjectively influenced by hedonic properties, as researchers are often reluctant to use unpleasant odors in deorphanization experiments. This problem could explain why most currently decoded receptors respond to pleasant odors. To reduce the complexity of the odor landscape, a focus on ecologically relevant (food) odors has been proposed, an approach that led to the identification of novel OR ligands (57, 58, 134,178).

In addition to the significant difficulties with the expression of heterologous ORs as a result of deficient expression on the cell surface (122,198), the activation efficiency of recombinantly expressed ORs may not reflect the responsiveness achieved by the expressed ORs. endogenously in vivo. This can have several reasons.

First, deorphanization by heterologously expressed ORs is an easy system to control, allowing control of the signaling pathway through overexpression of appropriate accessory proteins (156, 212), e.g. B. Gαolf, guanine nucleotide exchange factor B (Ric8b) (185, 186), and/or enables the CNGA2 channel (169). Other techniques based on recombinant expression of GPCRs in combination with Gαq subunits that activate IP3 signaling have been reported, including murine Gα15 or human Gα16 or chimeras of Gαolf and murine Gα15 (84, 98, 212). It has been suggested that the type of G protein is essential for an odorant to act as a receptor agonist or antagonist in a heterologous expression system(169). Despite the involvement of the G protein itself, OR sensitivity depends on the measurement technique, either by Ca2+ flux or cAMP level determination (eg, OR1A1/nonanal) (82,155,161). In addition to the involvement of various cellular signal transduction components, signal processing is influenced by a complex network of scaffolding proteins, phosphorylation events, and other potentially interacting proteins, such as non-olfactory GPCRs (13, 22). Therefore, it is not surprising that different cells show different or conflicting physiological responses to the same OR/odorant pair, as reported for ectopic OR2AT4; However, this problem complicates the study of ectopic surgical function.

Second, "artificial" OR expression systems can only partially mimic ORN functionality by co-expressing helper proteins to improve OR expression and activation efficiency, such as (REEP1)(2, 71, 98,106, 131, 142,156, 165) . Other modifications, such as NH2-terminal markers in the OR (eg, rho and lucy) (98, 165, 198) or coexpressed proteins (2), such as heat shock protein 70t (Hsc70t) (131), acetylcholine Muscarinic M3 receptor (M3) (106) and β2-adrenergic receptor (71) are not comparable to endogenously expressed ORs. However, significant advances were made with the development of the MouSensor assay system, which uses transgenic mice that express human OR in murine ORN(38).

Third, as discussed above, the question remains whether stronger (endogenous) agonists exist. Most of the studies relate to the characterization of ectopic ORs based on the use of odor concentrations at the supraphysiological level.

Fourth, the accessibility to tissues of exogenous odors varies significantly. Fabrics that are not in direct contact with the external environment, e.g. Exogenous chemicals, such as the kidneys and prostate, cannot easily reach them in reasonable concentrations. Therefore, the identification of potent activating agonists that are endogenous to the human body, such as hormones or metabolites, would greatly enrich this research topic. A prerequisite for the identification of very potent ligands is the structural investigation of the ligand-binding niche. The correlation between structure and odorant selectivity has been studied by site-directed mutagenesis and computer modeling to improve the identification of OR ligands (6, 28, 61, 100, 160, 161, 201, 202). Future prediction of the binding of ectopically expressed OR ligands using in silico approaches may facilitate the expansion of knowledge about their receptive field and accelerate the identification of more potent (endogenous) OR agonists.

The analysis of the protein expression of the ORs remains a great challenge. Due to the high sequence homology and difficulties in finding appropriate accessible epitopes on highly hydrophobic membrane proteins, the development of OR-specific antibodies is severely hampered. However, in recent years, several studies have demonstrated the expression of specific OR proteins by antibodies of high quality, specificity, and variable technical applicability (24, 26,34, 45, 48,49, 60, 70,82, 83,85 – 88, 93115, 116, 118119, 130, 132147, 179, 180191, 209). This at least offers the possibility of defining the function of ectopic ORs based on their subcellular location.

Whether the various physiological responses after scent application are definitely due to operating room activation is another challenge that needs to be resolved. For example, few studies have definitively shown that odor-induced physiological effects depend on specific OR activation by RNAi knockdown (24, 59, 85-88, 93, 119, 132, 179, 203, 209). These experiments are highly dependent on good transfection efficiencies; However, in most cellular systems, the transient transfection rate is < 5% and the effects are too small to allow quantification precisely enough to detect differences. Furthermore, the effect of RNAi is often incomplete, making assessment even more difficult. Therefore, it would be beneficial to establish more effective knockdown strategies (for example, gene editing via CRISPR/Cas) in future experiments.

Another powerful strategy to demonstrate the participation of a particular OR in the cellular response is the use of specific antagonists. However, only a few antagonists of human ORs have been identified, namely undecanal (OR1D2), α-ionone (OR51E2), oxyphenylone and phenirate (OR2AT4), methylcinnamaldehyde, hydrocinnamaldehyde, and bourgeois (OR3A1), which share structural similarities. generals with the OR. agonists (24, 79, 132, 173).

Current inactivation studies are difficult to perform because most human operating rooms do not have a clear ortholog in mice. The function of ectopic receptors may also vary between species, making it difficult to extrapolate the physiological function of human ORs to that of other mammals.

Therefore, identifying new operating room functions is quite challenging and technical improvements are needed to fill the gaps in scientific knowledge of the operating room function as a whole.

VIII EXPRESSION OF PERIPHERAL TISSUES OF OTHER MEMBERS OF THE OLACTORY SYSTEM

Another class of GPCRs with olfactory recognition in the nasal mucosa includes trace amine-associated receptors (TAARs) (11). TAARs are specifically activated by biogenic amines and have been suggested to function in pheromone sensing in mice (107). The human TAAR family comprises six member genes, four of which have been identified at the trait level in EO (27). However, there is considerable evidence that TAARs are expressed in peripheral human tissues outside of the EO (11,47). In addition to the initial identification in the mammalian brain (15), murine and human TAAR1 is absent from EO; however, it is used on various fabrics, e.g. B. blood, lung, ovary, testis, and brain tissue, widely expressed (10, 15, 47). In contrast, human TAAR5 is more abundant in human EO (135) and is also ectopically expressed at low levels in the human brain (47). It seems uncertain whether tissue expression is truly 'ectopic' (11) and may depend on the particular receptor. Recently, human TAARs expressed in the EO were shown to be functional. Human TAAR5 can be specifically activated by TMA, a volatile amine compound and the prototype of the "fishy" odor (187). As indicated for mice, it can be a molecular sensor for the detection of volatile amines in humans. An advantage of TAAR1 and TAAR5 is that their specific antagonists EPTTB [N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide] and timberol have been elucidated, respectively (16, 188). In addition, TMA is found in bodily secretions (167); therefore, human TAAR5 receptors can revive olfactory seeking for human social cues. However, knowledge of its physiological functions in human tissues beyond the cellular immune system is limited (5, 117). TAAR have been detected in blood lymphocytes (10,129), and TAAR1 and TAAR2 have been shown to be involved in immune functions in human (10) and primate (139) blood leukocytes. TAAR1 is functionally expressed in normal and malignant B cells and in a Burkitt's lymphoma cell line in which its receptor agonists have been suggested to induce apoptosis (190).

IX. CONCLUSIONS AND PERSPECTIVES FOR THE FUTURE

ROs are characterized by great structural diversity and are therefore very sensitive to many chemicals. Furthermore, ORs form the largest gene family in the mammalian genome. The finding that ORs are expressed at individually remarkable levels throughout the human body is justification enough to do everything possible to decipher their meaning. Their potential as important regulators in the multifaceted processing of chemical signals beyond the nose has been demonstrated in many tissues. Significant challenges remain regarding the elucidation of agonists and antagonists, the accessibility of olfactory tissue, and the decoding of the mechanisms of OR function; However, scientific interest and technical skills are advancing rapidly. Furthermore, decoding endogenous ligands for tissue-expressed ORs may improve our knowledge of receptor functions at the physiological level. Examples of pronounced expression of non-deorphanized receptors are OR6B3 in retina and TG and OR4N4 in sperm (48, 49, 83). Furthermore, improved ligand prediction using in silico approaches would help speed up the identification of all OR(201) bonding spectra. Since species overlap studies are inconclusive due to their differences described above, the development of alternative approaches using human environments is imperative. In addition, advances in bioartificial materials (tissue engineering) have made it possible to characterize ectopic OPs and more accurately simulate their actual physiological conditions in the future. Studies at the mRNA level are undoubtedly valuable for gaining an overview of the molecular basis of ORs; However, large-scale proteomics would facilitate the identification of potential interaction partners (13) to definitively understand the complex signaling that follows odorant-dependent activation, which has so far only been comprehensively studied for OR51E2 (200).

The functional significance of ectopic operating rooms is still not well understood. However, as presented here, its effect on carcinogenesis has been extensively demonstrated for various human cancers using in vitro and in vivo technologies in mice (1, 26, 50, 59, 88, 89, 115, 116, 118, 119, 132, 150, 158, 179, 191). In almost all cases studied so far, activation of tumor cells from OPs induces a significant decrease in proliferation or a complete arrest of tumor cell growth. Therefore, the idea of ​​the clinical utility of the use of ORs as biomarkers, which has been proposed for several ORs (34, 45, 62, 102, 132, 196, 205), should be expanded to develop promising clinical strategies in the future. It will also be interesting to decipher disease-associated OR functions after ligand-dependent activation. Therefore, the idea of ​​focusing on OPs for diagnostic and therapeutic approaches is feasible, since approximately 30% of currently used drugs act via rhodopsin-like GPCRs (138) and ORs are the largest subfamily. of GPCR. Most ORs can be detected in tissues outside the olfactory epithelium by transcriptome analysis. This points to an interesting and essential new group of important membrane proteins involved in cellular biological processes. Eliminating additional operating rooms will certainly increase the possibility of analyzing their detailed functions and identifying other potential targets that contribute to cancer initiation and progression.

Targeting ORs is conceivable not only for the treatment of cancer or other diseases, but also for pharmacological control of healthy cells because they positively affect cellular processes, as noted above for skin keratinocytes (24), melanocytes (60) and skin cells. respiratory tract (85). and in heart (82), kidney (87), intestine (17) and sperm (173).

The data provided here demonstrates the extranasal expression and functionality of operating rooms. One obvious implication of the fact that ORs have been identified outside of the nose is that they can no longer be seen as purely olfactory receptors, but as general chemoreceptors involved in physiological and pathophysiological processes throughout the human body. Furthermore, with around 400 members, ORs account for almost half of the GPCR proteins in humans, representing around 30% of the targets of all drugs used. In the future, some of the ORs are likely to have similar meanings to those of structurally related GPCRs, such as adrenergic or serotonergic receptors.

At present, however, numerous questions remain to be answered and more research is needed before fully enumerating the roles that ORs may play in various human tissues and in cancer pathology.

Some of the most important directions for current OR research include 1) identification of endogenous and physiologically relevant ligands; 2) identification of specific signaling pathways; 3) the characterization of the function of the RO in vivo; and 4) the application of active chemical compounds in operating rooms for clinical use (translational approach).

To solve these challenging problems, the following steps are required:

Extranasal expression from operating rooms is an exciting new area of ​​science that should attract young scientists based on recent and exciting discoveries. Since scientists compared only a handful of extranasal receptors (<10%) with the specific effects of activating compounds on human non-olfactory cells, there is enormous potential in untested ORs that require further characterization. This may include new and exciting information about important roles in physiological and pathophysiological processes. The use of aromas to treat serious health problems may be a distant dream that faces great challenges, but it represents a promising and little explored therapeutic area.

DISCLOSURE

The authors declare that they have no conflict of interest, financial or otherwise.

GRACIAS

We express our special thanks to Dr. G. Gisselmann for his constructive comments, helpful suggestions, and revisions.

Address for reprint orders and other correspondence: H. Hatt, Ruhr-Universität Bochum, Dept. of Cell Physiology, Universitätsstraße 150, D-44780 Bochum, Germany (email:Hans.[email protected]Von).

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How are olfactory receptors stimulated?

Each olfactory sensory neuron has only one type of receptor on its cilia, and the receptors are specialized to recognize specific odors, so bipolar neurons themselves are specialized.When an odorant binds to a receptor that recognizes itthe sensory neuron associated with the receptor is stimulated.

What stimulates the olfactory cells?

Olfactory or olfactory nerve cells are thus stimulated.the smells that surround us- the smell of a gardenia or the smell of baked bread. These nerve cells are located in a small patch of tissue at the top of the nose and connect directly to the brain.

How are olfactory cells activated?

After the odorant binds to the olfactory receptor, the receptor undergoes structural changes and binds to and activates the olfactory G protein within the olfactory receptor neuron. The G protein (G_alternativeof/you G_S) in turn activates the lyase, adenylate cyclase, which converts ATP to cyclic AMP (cAMP).