Trace amine-associated receptor

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"TAAR" redirects here. For other uses of "Taar", see Tar (string instrument) and Taar (film).

Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of

odorants in vertebrates.[9]

Animal TAAR complement

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

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
β-arrestin 2
leukocytes, elsewhere[note 2]
  •
blood glucose

 • Regulation of satiety & body weight 		 •
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)
testes
, leukocytes 		 • Periphery: 
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:
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
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. 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. ^
    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. premature stop codon – in the human TAAR9 gene occurs in 10–30% of individuals.[12][13]

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.[30][31][32]

See also

References

  1. PMID 11459929
    .
  2. PMID 11723224
    .
  3. ^
    PMID 21073468
    .
  4. PMID 26093041
    .
  5. ^
    S2CID 2389946
    .
  6. PMID 15860375
    .
  7. PMID 16451074
    .
  8. PMID 17888514
    .
  9. ^
    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. PMID 19237578
    .
  11. PMID 19325074
    .
  12. ^
    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. ^
    PMID 28723415
    .
  14. ^
    S2CID 2864195
    .
  15. ^ a b c d e f g h i j k "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. ^
    PMID 23315425
    .
  17. ^ a b "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. ^
    PMID 27424325
    .
  19. ^
    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. ISBN 978-3540389163
    .
  21. PMID 23393561
    .
  22. 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. PMID 25706283
    .
  24. ^
    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. PMID 35053262
    .
  27. PMID 25391046
    .
  28. 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. 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.

External links

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