Trace amine-associated receptor explained

Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001.^{[1] [2]} TAAR1, the first of six functional human TAARs, has gained considerable interest in academic and proprietary pharmaceutical research due to its role as the endogenous receptor for the trace amines phenethylamine, tyramine, and tryptamine – metabolic derivatives of the amino acids phenylalanine, tyrosine and tryptophan, respectively – ephedrine, as well as the synthetic psychostimulants, amphetamine, methamphetamine and methylenedioxymethamphetamine (MDMA, ecstasy).^{[3] [4] [5] [6] [7]} In 2004, it was shown that mammalian TAAR1 is also a receptor for thyronamines, decarboxylated and deiodinated relatives of thyroid hormones.^[4] TAAR2–TAAR9 function as olfactory receptors for volatile amine odorants in vertebrates.^[8]

Animal TAAR complement

The following is a list of the TAARs contained in selected animal genomes:^{[9] [10]}

• Human – 6 genes (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9) and 3 pseudogenes (TAAR3,,)
• Chimpanzee – 3 genes and 6 pseudogenes
• Mouse – 15 genes and 1 pseudogene
• Rat – 17 genes and 2 pseudogenes
• Zebrafish – 112 genes and 4 pseudogenes
• Frog – 3 genes and 0 pseudogenes
• Medaka – 25 genes and 1 pseudogenes
• Stickleback – 25 genes and 1 pseudogenes

Human trace amine-associated receptors

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.

TAAR
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Prior names	Signal transduction	Expression profile	Known or putative function in humans	Known ligands	Sources
hTAAR1	TA1 TAR1	,, GIRKs,	spinal cord Periphery: pancreatic , stomach, duodenum, intestines, leukocytes, elsewhere	CNS  modulation of monoamine/glutamate neurotransmission CNS: regulation of cognitive processes & mood states Periphery: leukocyte chemotaxis Periphery: regulation of GI hormone release & blood glucose Regulation of satiety & body weight	Trace amines (e.g., tyramine, PEA, NMPEA) Monoamine neurotransmitters (e.g., dopamine) Amphetamine and some structural analogs	^[11]
hTAAR2	GPR58	, other G protein coupling unknown	  Periphery: olfactory epithelium, intestines, heart, testes, leukocytes	Periphery: leukocyte chemotaxis Olfaction: chemoreceptor for volatile odorants		^[12] ^[13] ^[14] ^[15]
TAAR3	GPR57			Pseudogene in humans –		^[16]
TAAR4	TA2	N/A	N/A	Pseudogene in humans – N/A	N/A
hTAAR5	PNR	,, ,	CNS: brain (restricted), spinal cord Periphery: olfactory epithelium, intestines, testes, leukocytes	Olfaction: chemoreceptor for volatile & foul odorants	Agonists: trimethylamine, N,N-DMEA Inverse agonists: 3-iodothyronamine	^[17] ^[18] ^[19] ^[20]
hTAAR6	TA4 TAR4	, other G protein coupling unknown	CNS: brain Periphery: olfactory epithelium, intestines, testes, leukocytes, kidneys	Olfaction: chemoreceptor for volatile odorants	Agonists: putrescine and cadaverine^[21]	^[22]
TAAR7	–	N/A	N/A	Pseudogene in humans – N/A	N/A
hTAAR8	TA5 GPR102	, Gi/o	CNS: brain Periphery: olfactory epithelium, melanocytes,^[23] stomach, intestines, heart, testes, leukocytes, kidneys, lungs, muscle, spleen	Olfaction: chemoreceptor for volatile odorants	Agonists: putrescine and cadaverine	^[24]
hTAAR9	TA3 TAR3	, other G protein coupling unknown	CNS: spinal cord Periphery: olfactory epithelium, intestines, leukocytes, pituitary gland, skeletal muscle, spleen	Olfaction: chemoreceptor for volatile odorants	Agonist: N-Methyl piperidine (CAS: 626-67-5) ^[25]	^[26]
Notes

Disease links and clinical significance

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.^{[27] [28] [29]}

See also

• Olfactory receptor
• Odorant
• Pheromone
• Pheromone receptor
• Psychostimulant
• Thyronamine
• Trace amine

External links

• Web site: Trace Amine Receptors . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C . 6 . Trace amines: identification of a family of mammalian G protein-coupled receptors . Proceedings of the National Academy of Sciences of the United States of America . 98 . 16 . 8966–8971 . July 2001 . 11459929 . 55357 . 10.1073/pnas.151105198 . free .
2. Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK . 6 . 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 . December 2001 . 11723224 . 10.1124/mol.60.6.1181 .
3. Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A . In-vivo pharmacology of Trace-Amine Associated Receptor 1 . European Journal of Pharmacology . 763 . Pt B . 136–142 . September 2015 . 26093041 . 10.1016/j.ejphar.2015.06.026 .
4. Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK . 6 . 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone . Nature Medicine . 10 . 6 . 638–642 . June 2004 . 15146179 . 10.1038/nm1051 . 2389946 .
5. Lindemann L, Hoener MC . A renaissance in trace amines inspired by a novel GPCR family . Trends in Pharmacological Sciences . 26 . 5 . 274–281 . May 2005 . 15860375 . 10.1016/j.tips.2005.03.007 .
6. Hart ME, Suchland KL, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS . Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues . Journal of Medicinal Chemistry . 49 . 3 . 1101–1112 . February 2006 . 16451074 . 10.1021/jm0505718 .
7. Grandy DK . Trace amine-associated receptor 1-Family archetype or iconoclast? . Pharmacology & Therapeutics . 116 . 3 . 355–390 . December 2007 . 17888514 . 2767338 . 10.1016/j.pharmthera.2007.06.007 .
8. Liberles SD . Trace amine-associated receptors: ligands, neural circuits, and behaviors . Current Opinion in Neurobiology . 34 . 1–7 . October 2015 . 25616211 . 4508243 . 10.1016/j.conb.2015.01.001 . 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
9. Hussain A, Saraiva LR, Korsching SI . Positive Darwinian selection and the birth of an olfactory receptor clade in teleosts . Proceedings of the National Academy of Sciences of the United States of America . 106 . 11 . 4313–4318 . March 2009 . 19237578 . 2657432 . 10.1073/pnas.0803229106 . 2009PNAS..106.4313H . free .
10. Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP . International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature . Pharmacological Reviews . 61 . 1 . 1–8 . March 2009 . 19325074 . 2830119 . 10.1124/pr.109.001107 .
11. Miller GM . The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity . Journal of Neurochemistry . 116 . 2 . 164–176 . January 2011 . 21073468 . 3005101 . 10.1111/j.1471-4159.2010.07109.x .
12. Web site: Trace amine receptor: Introduction. International Union of Basic and Clinical Pharmacology. 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..
13. Babusyte A, Kotthoff M, Fiedler J, Krautwurst D . Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2 . Journal of Leukocyte Biology . 93 . 3 . 387–394 . March 2013 . 23315425 . 10.1189/jlb.0912433 . free .
14. Web site: TAAR2. International Union of Basic and Clinical Pharmacology. 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..
15. Khan MZ, Nawaz W . The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system . Biomedicine & Pharmacotherapy . 83 . 439–449 . October 2016 . 27424325 . 10.1016/j.biopha.2016.07.002 .
16. Berry MD, Gainetdinov RR, Hoener MC, Shahid M . Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges . Pharmacology & Therapeutics . 180 . 161–180 . December 2017 . 28723415 . 10.1016/j.pharmthera.2017.07.002 . free .
17. Book: Offermanns, Stefan. Encyclopedia of Molecular Pharmacology . limited. 2008 . Springer . Berlin . 978-3540389163 . 1219–1222 . 2nd . Walter Rosenthal.
18. Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, Becker C, Schmidt A, Hatt H, Hummel T, Gisselmann G . 6 . Human trace amine-associated receptor TAAR5 can be activated by trimethylamine . PLOS ONE . 8 . 2 . e54950 . 2013 . 23393561 . 3564852 . 10.1371/journal.pone.0054950 . 2013PLoSO...854950W . free .
19. Zhang J, Pacifico R, Cawley D, Feinstein P, Bozza T . Ultrasensitive detection of amines by a trace amine-associated receptor . The Journal of Neuroscience . 33 . 7 . 3228–3239 . February 2013 . 23407976 . 3711460 . 10.1523/JNEUROSCI.4299-12.2013 . We show that [human TAAR5] responds to the tertiary amine N,N-dimethylethylamine and to a lesser extent to trimethylamine, a structurally related agonist for mouse and rat TAAR5 (Liberles and Buck, 2006; Staubert et al., 2010; Ferrero et al., 2012). .
20. Dinter J, Mühlhaus J, Wienchol CL, Yi CX, Nürnberg D, Morin S, Grüters A, Köhrle J, Schöneberg T, Tschöp M, Krude H, Kleinau G, Biebermann H . 6 . Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5 . PLOS ONE . 10 . 2 . e0117774 . 2015 . 25706283 . 4382497 . 10.1371/journal.pone.0117774 . 2015PLoSO..1017774D . free .
21. Izquierdo C, Gómez-Tamayo JC, Nebel JC, Pardo L, Gonzalez A . Identifying human diamine sensors for death related putrescine and cadaverine molecules . PLOS Computational Biology . 14 . 1 . e1005945 . January 2018 . 29324768 . 5783396 . 10.1371/journal.pcbi.1005945 . 2018PLSCB..14E5945I . free .
22. Web site: TAAR6. International Union of Basic and Clinical Pharmacology. 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.
23. Vaganova AN, Kuvarzin SR, Sycheva AM, Gainetdinov RR . Deregulation of Trace Amine-Associated Receptors (TAAR) Expression and Signaling Mode in Melanoma . Biomolecules . 12 . 1 . 114 . January 2022 . 35053262 . 10.3390/biom12010114 . 8774021 . free .
24. Mühlhaus J, Dinter J, Nürnberg D, Rehders M, Depke M, Golchert J, Homuth G, Yi CX, Morin S, Köhrle J, Brix K, Tschöp M, Kleinau G, Biebermann H . 6 . Analysis of human TAAR8 and murine Taar8b mediated signaling pathways and expression profile . International Journal of Molecular Sciences . 15 . 11 . 20638–20655 . November 2014 . 25391046 . 4264187 . 10.3390/ijms151120638 . free .
25. Liberles SD . Trace amine-associated receptors: ligands, neural circuits, and behaviors . Current Opinion in Neurobiology . 34 . 1–7 . October 2015 . 25616211 . 4508243 . 10.1016/j.conb.2015.01.001 .
26. Web site: TAAR9. International Union of Basic and Clinical Pharmacology. 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]..
27. Heffernan ML, Herman LW, Brown S, Jones PG, Shao L, Hewitt MC, Campbell JE, Dedic N, Hopkins SC, Koblan KS, Xie L . 6 . Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia . ACS Medicinal Chemistry Letters . 13 . 1 . 92–98 . January 2022 . 35047111 . 8762745 . 10.1021/acsmedchemlett.1c00527 .
28. Web site: Sunovion: creating therapies to help transform people's lives . 2022-06-04 . www.sunovion.com.
29. Web site: Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia . 2022-06-04 . news.sunovion.com . en-US.