Six human trace amine-associated receptors (hTAARs) – hTAAR1, hTAAR2, hTAAR5, hTAAR6, hTAAR8, and hTAAR9 – have been identified and partially characterized. The table below contains summary information from literature reviews, pharmacology databases, and supplementary primary research articles on the expression profiles, signal transduction mechanisms, ligands, and physiological functions of these receptors.
The pharmacology and molecular biology of human trace amine-associated receptors
^As of December 2017,[update] the functions of hTAAR2, hTAAR5, hTAAR6, hTAAR8, and hTAAR9 in the CNS and peripheral tissues outside the olfactory epithelium have not been determined.[13]
^hTAAR1 is the only TAAR subtype that is not expressed within the human olfactory epithelium.[9][14] Hence, unlike all other human trace amine-associated receptors, hTAAR1 does not function as an olfactory receptor in humans.[9][14]
A review of studies involving non-human animals indicated that TAARs in the olfactory epithelium can mediate attractive or aversive behavioral responses to an agonist.[9] This review also noted that the behavioral response evoked by a TAAR can vary across species.[9] For example, TAAR5 mediates attraction to trimethylamine in mice and aversion to trimethylamine in rats.[9] In humans, hTAAR5 presumably mediates aversion to trimethylamine, which is known to act as an hTAAR5 agonist and to possess a foul, fishy odor that is aversive to humans;[9][19] however, hTAAR5 is not the only olfactory receptor that is responsible for trimethylamine olfaction in humans.[9][19] As of December 2015,[update] hTAAR5-mediated trimethylamine aversion has not been examined in published research.[19]
Ulotaront / SEP 363856 is a TAAR1 agonist in phase 3 clinical trials for schizophrenia and earlier trials for Parkinson's Disease psychosis. The medicine has obtained Breakthrough designation from the US FDA.[30][31][32]
This section needs expansion with: coverage of relevant material from this review[13]. You can help by adding to it. (March 2018)
^Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. (December 2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Molecular Pharmacology. 60 (6): 1181–1188. doi:10.1124/mol.60.6.1181. PMID11723224.
^Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (September 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1". European Journal of Pharmacology. 763 (Pt B): 136–142. doi:10.1016/j.ejphar.2015.06.026. PMID26093041.
^ abScanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, et al. (June 2004). "3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone". Nature Medicine. 10 (6): 638–642. doi:10.1038/nm1051. PMID15146179. S2CID2389946.
^Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID15860375.
^Hart ME, Suchland KL, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS (February 2006). "Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues". Journal of Medicinal Chemistry. 49 (3): 1101–1112. doi:10.1021/jm0505718. PMID16451074.
^ abcdefghijklmnopLiberles SD (October 2015). "Trace amine-associated receptors: ligands, neural circuits, and behaviors". Current Opinion in Neurobiology. 34: 1–7. doi:10.1016/j.conb.2015.01.001. PMC4508243. PMID25616211. Roles for another receptor are supported by TAAR5-independent trimethylamine anosmias in humans [32]. ... Several TAARs detect volatile and aversive amines, but the olfactory system is capable of discarding ligand-based or function-based constraints on TAAR evolution. Particular TAARs have mutated to recognize new ligands, with almost an entire teleost clade losing the canonical amine-recognition motif. Furthermore, while some TAARs detect aversive odors, TAAR-mediated behaviors can vary across species. ... The ability of particular TAARs to mediate aversion and attraction behavior provides an exciting opportunity for mechanistic unraveling of odor valence encoding. Figure 2: Table of ligands, expression patterns, and species-specific behavioral responses for each TAAR
^ abcdeDavenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, et al. (July 2013). "International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands". Pharmacological Reviews. 65 (3): 967–986. doi:10.1124/pr.112.007179. PMC3698937. PMID23686350. TAAR2 and TAAR9 Two of the trace amine receptors are inactivated in a portion of the human population. There is a polymorphism in TAAR2 (rs8192646) producing a premature stop codon at amino acid 168 in 10–15% of Asians. TAAR9 (formerly TRAR3) appears to be functional in most individuals but has a polymorphic premature stop codon at amino acid 61 (rs2842899) with an allele frequency of 10–30% in different populations (Vanti et al., 2003). TAAR3 (formerly GPR57) and TAAR4 (current gene symbol, TAAR4P) are thought to be pseudogenes in man though functional in rodents (Lindemann et al., 2005).
^ abcdefghijk"Trace amine receptor: Introduction". International Union of Basic and Clinical Pharmacology. Retrieved 15 February 2014. Importantly, three ligands identified activating mouse Taars are natural components of mouse urine, a major source of social cues in rodents. Mouse Taar4 recognizes β-phenylethylamine, a compound whose elevation in urine is correlated with increases in stress and stress responses in both rodents and humans. Both mouse Taar3 and Taar5 detect compounds (isoamylamine and trimethylamine, respectively) that are enriched in male versus female mouse urine. Isoamylamine in male urine is reported to act as a pheromone, accelerating puberty onset in female mice [34]. The authors suggest the Taar family has a chemosensory function that is distinct from odorant receptors with a role associated with the detection of social cues. ... The evolutionary pattern of the TAAR gene family is characterized by lineage-specific phylogenetic clustering [26,30,35]. These characteristics are very similar to those observed in the olfactory GPCRs and vomeronasal (V1R, V2R) GPCR gene families.
^ ab"TAAR2". International Union of Basic and Clinical Pharmacology. Retrieved 15 May 2018. Primary Transduction Mechanisms Comments: TAAR2 is found to be coexpressed with Gα proteins. However, the transduction pathway of TAAR2 is yet to be determined.
^ abKhan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomedicine & Pharmacotherapy. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. PMID27424325.
^ abcWallrabenstein I, Singer M, Panten J, Hatt H, Gisselmann G (2015). "Timberol® Inhibits TAAR5-Mediated Responses to Trimethylamine and Influences the Olfactory Threshold in Humans". PLOS ONE. 10 (12): e0144704. Bibcode:2015PLoSO..1044704W. doi:10.1371/journal.pone.0144704. PMC4684214. PMID26684881. While mice produce gender-specific amounts of urinary TMA levels and were attracted by TMA, this odor is repellent to rats and aversive to humans [19], indicating that there must be species-specific functions. ... Furthermore, a homozygous knockout of murine TAAR5 abolished the attraction behavior to TMA [19]. Thus, it is concluded that TAAR5 itself is sufficient to mediate a behavioral response at least in mice. ... Whether the TAAR5 activation by TMA elicits specific behavioral output like avoidance behavior in humans still needs to be examined.
^"TAAR6". International Union of Basic and Clinical Pharmacology. Retrieved 15 May 2018. Tissue Distribution Kidney, amygdala, hippocampus; Species: Human; Technique: RT-PCR ... Human brain tissues (with the level of expression descending from hippocampus, substantia nigra, amygdala, frontal cortex to basal ganglia), human fetal liver. Not detected in the cerebellum or placenta.; Species: Human; Technique: RT-PCR
^"TAAR9". International Union of Basic and Clinical Pharmacology. Retrieved 15 May 2018. Tissue Distribution Comments ... No expression of TAAR9 was detected by RT-PCR in the Grueneberg ganglion [2]. TAAR9 expression was not detected by Northern blot analysis in thalamus, amygdala, midbrain, hippocampus, putamen, caudate, frontal cortex, pons, prostate, stomach, heart, bladder, small intestine, colon or uterus [4].
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as the List of trace amines, TAAR, and TAAR1 pages. See also:Receptor/signaling modulators
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