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Pheromone Receptors and Their Putative Ligands: Possible Role in Humans V

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Pheromone Receptors and Their Putative Ligands: Possible Role in Humans V European Review for Medical and Pharmacological Sciences 2020; 24: 2140-2150 Pheromone receptors and their putative ligands: possible role in humans V. PRECONE1, S. PAOLACCI2, T. BECCARI3, L. DALLA RAGIONE4, L. STUPPIA5, M. BAGLIVO2, G. GUERRI2, E. MANARA1, G. TONINI6, K.L. HERBST7, V. UNFER8, M. BERTELLI1,2,9 1MAGI Euregio, Bolzano, Italy 2MAGI’s Lab, Rovereto (TN), Italy 3Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy 4Center for the Treatment of Eating Disorders Residenza Palazzo Francisci, Todi (PG), Italy 5Department of Psychological, Health and Regional Sciences, School of Medicine and Health Sciences, University G. D’Annunzio, Chieti, Italy 6Department of Urology, Poliambulanza Foundation, Brescia, Italy 7Departments of Medicine, Pharmacy, Medical Imaging, Division of Endocrinology, University of Arizona, Tucson, AZ, USA 8Department of Developmental and Social Psychology, Faculty of Medicine and Psychology, University of Rome Sapienza, Rome, Italy 9EBTNA-LAB, Rovereto (TN), Italy Abstract. Pheromones are ectohormones Introduction that play an important role in communication and behavior. Pheromones and pheromone re- Pheromones are secreted chemical messengers ceptor genes are important in mice and other that act like hormones outside the body, trigger- mammals that rely heavily on pheromone cues to survive. Although there is controversy about ing signals between individuals of the same spe- whether pheromones and pheromone receptor cies and affecting the behavior of those receiving genes have the same importance or are even ac- the signals1. To establish whether a molecule is ac- tive in humans, there are some hints that they tually a pheromone it is necessary to use repeat- might have roles in sociosexual behavior and able experiments designed to measure a biolog- mental disorders. The aim of this qualitative re- ical response (bioassays). Since these bioassays view was to provide an overview of the state of the art regarding pheromones and pheromone have only been designed for animal pheromones, receptors in humans and their possible implica- the prospect of pheromone communication in hu- 2 tions in human physiology and pathology. mans has so far been controversial . An electronic search was conducted in MED- In 2014, Wyatt1 proposed a series of criteria for LINE, PubMed and Scopus databases for arti- the definition of pheromones: a synthetic pheromone cles published in English up to December 2018. should trigger the same response as the natural stim- The search concerned a possible role of pher- ulus in a bioassay; it should be functional at natu- omones and pheromone receptors in humans with implications for sociosexual behavior, men- ral concentrations; in the case of a multicomponent tal disorders, the menstrual cycle and nutrition. pheromone, all components in combination should Pheromone communication in humans has not be necessary and sufficient to generate the com- been definitively demonstrated. However, the po- plete response; only that molecule/combination of tential ability of putative pheromones to activate molecules should elicit the effect; and finally, there the hypothalamus, which controls the release of should be a credible pathway for the pheromone sig- many hormones, suggests they could have a role 1 in systemic functions in humans. Future confirma- nal to have evolved by natural selection . tion of the effects of pheromones and pheromone It is difficult to study human pheromones be- receptors in humans could be useful in the pre- cause many human scents are produced by bac- vention and treatment of various human disorders. teria and other microorganisms which confound Key Words: the results. The existence of pheromones is there- Human pheromone, Vomeronasal receptor, Trace fore not yet clearly demonstrated in humans, and amine associated receptor, Pheromone exogenous no reproducible bioassays have been designed to steroid receptor. study pheromone communication in humans. 2140 Corresponding Author: Stefano Paolacci, Ph.D; e-mail: [email protected] Pheromone receptors and their putative ligands: possible role in humans The best candidates for human pheromones lack the VNO-formyl peptide receptors, TAAR3, are the secretions produced by lactating mothers. TAAR4 and TAAR7. Phenotypes of knockout It seems that babies suck in response to secretions mice for genes encoding VRs and TAARs are from the areola gland around the nipple3. Unlike useful for understanding the roles of pheromones odors, these hormone-like scents may activate a (Figure 1)5-7. specific area of the human brain: the hypothala- Vomeronasal receptors (VRs) are classified mus4. The hypothalamus is a gland that secretes into two major groups, V1Rs and V2Rs. In hu- a number of hormones, including gonadotropin mans, only V1Rs are encoded by functional releasing hormone, important in sex steroid se- genes. V1Rs are class A GPCRs, however they cretion. The aim of this qualitative review was to have no significant sequence homology with oth- provide an update on the state of the art regarding er receptors of this class. The ligand binding sites pheromones and pheromone receptors in humans are located in transmembrane regions. Vomero- and their possible implications in physiological nasal sensory neurons have several subunits of and pathological conditions. heterotrimeric G proteins: Gγ2 associates with V1Rs. The ligand induces a cascade that leads to the synthesis of diacylglycerol that in turn induc- Materials and Methods es opening of the transient receptor potential cal- cium channel8. This paper is a qualitative review of all orig- The TAARs belong to a group of GPCRs inal research papers on pheromones published in characterized by distinct sequence motifs. They scientific journals. It focuses on the roles of phero- are activated by trace amines, such as β-phenyl- mones in physiological and pathological states. An ethylamine, p-tyramine, tryptamine and octopa- electronic search was conducted in MEDLINE, mine. They have a structure typical of the rho- PubMed database and Scopus using combinations dopsin/β-adrenergic receptor superfamily. There of the following search terms: “pheromones in are few distinct TAAR subtypes (15 in mice; 6 in humans”, “human pheromone receptors”, “vom- humans). TAARs are associated with G proteins eronasal receptors”, “trace amine associated re- Gαolf and Gαi2, which activate adenylate cyclase, ceptors”, “pheromone exogenous steroid recep- triggering two pathways: G-protein-dependent tors”, “pheromones and nutrition”, “pheromones stimulation of protein kinase A/C, and G-pro- and psychiatric disorders” and “pheromones and tein independent activation of protein kinase B menstruation”. Inclusion criteria required the (AKT)/glycogen synthase kinase 3β8. term or topic “pheromones” in the title or abstract. Pheromone receptors are expressed in differ- Articles were included if they contained detailed ent types of tissue in humans and mice, suggest- data on cohorts of patients and/or animal models. ing different functions of pheromone receptors in Reference lists were scanned to retrieve addition- the two species. However, mice-to-human studies al relevant articles. A comprehensive systematic do help identify the putative role of pheromones manual selection of articles identified as relevant in human sociosexual behavior and their implica- for this review aimed to include as many studies tions in various diseases. The main functional VR as possible. The selection was limited to articles and TAAR receptors in humans are described be- in English. The screening process was conducted low, along with their different locations in tissues independently by all authors. Disagreements on of mice and humans (Table I). the conclusions of papers were settled through discussion until consensus. The final search was Mammalian Vomeronasal Receptors conducted in December 2018. In mammalian pheromone transduction, sen- sory neurons are located in the olfactory sys- tem (that forms from main olfactory epithelium, Results MOE), the vomeronasal organ (VNO), the Gruen- eberg ganglion (GG) and the septal organ (SO), Mouse and Human Pheromone which in turn express chemosensory receptors Receptors and project axons to the olfactory bulb to stim- Mice and humans have vomeronasal receptors ulate distinct limbic circuits. Mammalian pher- (VRs) and trace amine associated receptors (TA- omones are mainly detected by the peripheral ARs), but the intact and active genes encoding sensory organ of the accessory olfactory VNO22. VRs and TAARs differ between them, humans After embryogenesis, the VNO regresses in hu- 2141 V. Precone, S. Paolacci, T. Beccari, L. Dalla Ragione, L. Stuppia, et al. Figure 1. A, Venn diagram show- ing vomeronasal receptors (VRs) and trace amine associated receptors (TA- ARs) in mice and humans. B, Number of intact and non-intact genes, includ- ing pseudogenes and potentially intact genes (in parentheses), concerned with VRs and TAARs in humans and mice. C, Phenotypes of knockout mice for VR and TAAR receptor genes. VNO- FPR = vomeronasal organ formyl pep- tide receptor. A B C mans23. However, it has been demonstrated that Finally, in mice, there is a third category of sev- this small VNO pouch is functional and responds en-pass transmembrane domain receptors, encoded to chemicals, altering autonomic processes. It has by the V3R gene family, predicted to function as been postulated that these effects occur through pheromone receptors and including about 100 to 120 stimulation of
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