Trace amine-associated receptor

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 phenylethylamine, 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][8] In 2004, it was shown that mammalian TAAR1 is also a receptor for thyronamines, decarboxylated and deiodinated relatives of thyroid hormones.[5] TAAR2–TAAR9 function as olfactory receptors for volatile amine odorants in vertebrates.[9]

Animal TAAR complement

The following is a list of the TAARs contained in selected animal genomes:[10][11]

  • Human – 6 genes (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9) and 3 pseudogenes (TAAR3, TAAR4P, TAAR7P)[12]
  • 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.

The pharmacology and molecular biology of human trace amine-associated receptors
TAAR
subtype		 Prior
names		 Signal
transduction		 Expression
profile		 Known or putative function in humans[note 1] Known ligands Sources
hTAAR1 TA1
TAR1		 Gs, Gq,
GIRKs,
β-arrestin 2		 CNS: brain (widespread), spinal cord
Periphery: pancreatic β-cells, stomach, duodenum, intestines, leukocytes, elsewhere[note 2]		  • 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		 [3][13]
[15][16]
hTAAR2
[note 3]		 GPR58 Golf, other G protein coupling unknown[note 4] CNS: brain (restricted)[note 5] 
Periphery: olfactory epithelium, intestines, heart, testes, leukocytes		  • Periphery: leukocyte chemotaxis
 • Olfaction: chemoreceptor for volatile odorants[note 6]
 [9][13]
[15][16]
[17][18]
TAAR3 GPR57 N/A N/A Pseudogene in humans – N/A N/A [12][13]
[15]
TAAR4 TA2 N/A N/A Pseudogene in humans – N/A N/A [12][13]
[15]
hTAAR5 PNR Gs, Golf,
Gq, G12/13		 CNS: brain (restricted),
spinal cord
Periphery: olfactory epithelium, intestines, testes, leukocytes		  • Olfaction: chemoreceptor for volatile & foul odorants[note 6]  • Agonists: trimethylamine, N,N-DMEA
 • Inverse agonists: 3-iodothyronamine		 [9][13]
[15][20]
[21][22]
[23]
hTAAR6 TA4
TAR4		 Golf, other G protein coupling unknown CNS: brain
Periphery: olfactory epithelium, intestines, testes, leukocytes, kidneys		  • Olfaction: chemoreceptor for volatile odorants[note 6]  • Agonists: putrescine and cadaverine[24] [9][13]
[15][25]
TAAR7 – N/A N/A Pseudogene in humans – N/A N/A [9][13]
[15]
hTAAR8 TA5
GPR102		 Golf, Gi/o CNS: brain
Periphery: olfactory epithelium, melanocytes,[26] stomach, intestines, heart, testes, leukocytes, kidneys, lungs, muscle, spleen		  • Olfaction: chemoreceptor for volatile odorants[note 6]  • Agonists: putrescine and cadaverine[24] [9][13]
[15][27]
hTAAR9
[note 7]		 TA3
TAR3		 Golf, other G protein coupling unknown CNS: spinal cord
Periphery: olfactory epithelium, intestines, leukocytes, pituitary gland, skeletal muscle, spleen		  • Olfaction: chemoreceptor for volatile odorants[note 6]  • Agonist: N-Methyl piperidine (CAS: 626-67-5) [28] [9][13]
[15][29]
Notes
  1. As of December 2017, the functions of hTAAR2, hTAAR5, hTAAR6, hTAAR8, and hTAAR9 in the CNS and peripheral tissues outside the olfactory epithelium have not been determined.[13]
  2. 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]
  3. hTAAR2 is a non-functional receptor in 10–15% of Asians due to the occurrence of a single-nucleotide polymorphism involving a premature stop codon in the human TAAR2 gene.[12][13]
  4. hTAAR2 has been found to be coexpressed with Gα proteins, however its exact signal transduction mechanisms have not yet been established.[13][17]
  5. hTAAR2 expression has been observed in the human cerebellum.[18]
  6. In humans and other animals, TAARs that are expressed in the olfactory epithelium function as olfactory receptors that detect volatile amine odorants, including certain pheromones;[9][15] these TAARs putatively function as a class of pheromone receptors involved in the olfactive detection of social cues.[9][15]

    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, hTAAR5-mediated trimethylamine aversion has not been examined in published research.[19]
  7. hTAAR9 is a functional receptor in most individuals, but a loss-of-function mutation – specifically, a polymorphic premature stop codon – in the human TAAR9 gene occurs in 10–30% of individuals.[12][13]

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]

See also

References
  1. Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. (July 2001). "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. doi:10.1073/pnas.151105198. PMC 55357. PMID 11459929.
  2. 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. PMID 11723224.
  3. Miller GM (January 2011). "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. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
  4. 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. PMID 26093041.
  5. Scanlan 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. PMID 15146179. S2CID 2389946.
  6. 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. PMID 15860375.
  7. 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. PMID 16451074.
  8. Grandy DK (December 2007). "Trace amine-associated receptor 1-Family archetype or iconoclast?". Pharmacology & Therapeutics. 116 (3): 355–390. doi:10.1016/j.pharmthera.2007.06.007. PMC 2767338. PMID 17888514.
  9. Liberles 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. PMC 4508243. PMID 25616211. 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
  10. Hussain A, Saraiva LR, Korsching SI (March 2009). "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. Bibcode:2009PNAS..106.4313H. doi:10.1073/pnas.0803229106. PMC 2657432. PMID 19237578.
  11. Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP (March 2009). "International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature". Pharmacological Reviews. 61 (1): 1–8. doi:10.1124/pr.109.001107. PMC 2830119. PMID 19325074.
  12. Davenport 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. PMC 3698937. PMID 23686350. 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).
  13. Berry MD, Gainetdinov RR, Hoener MC, Shahid M (December 2017). "Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges". Pharmacology & Therapeutics. 180: 161–180. doi:10.1016/j.pharmthera.2017.07.002. PMID 28723415.
  14. Liberles SD, Buck LB (August 2006). "A second class of chemosensory receptors in the olfactory epithelium". Nature. 442 (7103): 645–650. Bibcode:2006Natur.442..645L. doi:10.1038/nature05066. PMID 16878137. S2CID 2864195.
  15. "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.
  16. Babusyte A, Kotthoff M, Fiedler J, Krautwurst D (March 2013). "Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2". Journal of Leukocyte Biology. 93 (3): 387–394. doi:10.1189/jlb.0912433. PMID 23315425.
  17. "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.
  18. Khan 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. PMID 27424325.
  19. Wallrabenstein 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. PMC 4684214. PMID 26684881. 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.
  20. Offermanns, Stefan (2008). Walter Rosenthal (ed.). Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222. ISBN 978-3540389163.
  21. Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, et al. (2013). "Human trace amine-associated receptor TAAR5 can be activated by trimethylamine". PLOS ONE. 8 (2): e54950. Bibcode:2013PLoSO...854950W. doi:10.1371/journal.pone.0054950. PMC 3564852. PMID 23393561.
  22. Zhang J, Pacifico R, Cawley D, Feinstein P, Bozza T (February 2013). "Ultrasensitive detection of amines by a trace amine-associated receptor". The Journal of Neuroscience. 33 (7): 3228–3239. doi:10.1523/JNEUROSCI.4299-12.2013. PMC 3711460. PMID 23407976. 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).
  23. Dinter J, Mühlhaus J, Wienchol CL, Yi CX, Nürnberg D, Morin S, et al. (2015). "Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5". PLOS ONE. 10 (2): e0117774. Bibcode:2015PLoSO..1017774D. doi:10.1371/journal.pone.0117774. PMC 4382497. PMID 25706283.
  24. Izquierdo C, Gómez-Tamayo JC, Nebel JC, Pardo L, Gonzalez A (January 2018). "Identifying human diamine sensors for death related putrescine and cadaverine molecules". PLOS Computational Biology. 14 (1): e1005945. Bibcode:2018PLSCB..14E5945I. doi:10.1371/journal.pcbi.1005945. PMC 5783396. PMID 29324768.
  25. "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
  26. Vaganova AN, Kuvarzin SR, Sycheva AM, Gainetdinov RR (January 2022). "Deregulation of Trace Amine-Associated Receptors (TAAR) Expression and Signaling Mode in Melanoma". Biomolecules. 12 (1): 114. doi:10.3390/biom12010114. PMC 8774021. PMID 35053262.
  27. Mühlhaus J, Dinter J, Nürnberg D, Rehders M, Depke M, Golchert J, et al. (November 2014). "Analysis of human TAAR8 and murine Taar8b mediated signaling pathways and expression profile". International Journal of Molecular Sciences. 15 (11): 20638–20655. doi:10.3390/ijms151120638. PMC 4264187. PMID 25391046.
  28. Liberles 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. PMC 4508243. PMID 25616211.
  29. "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].
  30. Heffernan ML, Herman LW, Brown S, Jones PG, Shao L, Hewitt MC, et al. (January 2022). "Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia". ACS Medicinal Chemistry Letters. 13 (1): 92–98. doi:10.1021/acsmedchemlett.1c00527. PMC 8762745. PMID 35047111.
  31. "Sunovion: creating therapies to help transform people's lives". www.sunovion.com. Retrieved 4 June 2022.
  32. "Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia". news.sunovion.com. Retrieved 4 June 2022.
  • "Trace Amine Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
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