| 释义 |
- Animal TAAR complement
- Human trace amine-associated receptors Disease links and clinical significance
- See also
- References
- External links
{{redirect|TAAR|the musical instrument|Taar}}{{Use dmy dates|date=March 2014}}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).[4][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), 2 pseudogenes ({{Gene|TAAR4P}}, {{Gene|TAAR7P}}), and one probable pseudogene (TAAR3)[14]
- 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 receptorsSix 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 receptorsTAAR
subtype | Prior
names | Signal
transduction | Expression
profile | Known or putative function in humans{{#tag:ref|{{As of|December 2017|post=, the functions of hTAAR2, hTAAR5, hTAAR6, hTAAR8, and hTAAR9 in the CNS and peripheral tissues outside the olfactory epithelium have not been determined.[15]|group="note" | Known ligands | Sources | | hTAAR1 | TA1
TAR1 | {{nowrap|Gs}}, {{nowrap|Gq}},
GIRKs,
{{nowrap|β-arrestin 2}} | CNS: brain (widespread),}} spinal cord
Periphery: pancreatic {{nowrap|β-cells}}, stomach, duodenum, intestines, leukocytes, elsewhere{{#tag:ref|hTAAR1 is the only TAAR subtype that is not expressed within the human olfactory epithelium.[8][11] Hence, unlike all other human trace amine-associated receptors, hTAAR1 does not function as an olfactory receptor in humans.[8][11]|group="note"}} | {{bull}}CNS: modulation of monoamine/glutamate neurotransmission
{{bull}}CNS: regulation of cognitive processes & mood states
{{bull}}Periphery: leukocyte chemotaxis
{{bull}}Periphery: regulation of GI hormone release & blood glucose
{{bull}}Regulation of satiety & body weight | {{bull}}Trace amines (e.g., tyramine, PEA, NMPEA)
{{bull}}Monoamine neurotransmitters (e.g., dopamine)
{{bull}}Amphetamine and some structural analogs | [12][15]
[22][23] |
|---|
hTAAR2
{{#tag:ref|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.[14][15]|group="note" | GPR58 | {{nowrap|Golf}}, other G protein coupling unknown{{#tag:ref|hTAAR2 has been found to be coexpressed with Gα proteins, however its exact signal transduction mechanisms have not yet been established.[15][27]|group="note"}} | CNS: brain (restricted){{#tag:ref|hTAAR2 expression has been observed in the human cerebellum.[28]|group="note"}}}}
Periphery: olfactory epithelium, intestines, heart, testes, leukocytes | {{bull}}Periphery: leukocyte chemotaxis
{{bull}}Olfaction: chemoreceptor for volatile odorants{{#tag:ref|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;[8][22] these TAARs putatively function as a class of pheromone receptors involved in the olfactive detection of social cues.[8][22]
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.[8] This review also noted that the behavioral response evoked by a TAAR can vary across species.[8] For example, TAAR5 mediates attraction to trimethylamine in mice and aversion to trimethylamine in rats.[8] 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;[8][13] however, hTAAR5 is not the only olfactory receptor that is responsible for trimethylamine olfaction in humans.[8][13] {{As of|December 2015|post=,}} hTAAR5-mediated trimethylamine aversion has not been examined in published research.[13]|name="pheromone"|group="note"}}
| | [8][15]
[14][15]
[16][17] |
|---|
| TAAR3 | GPR57 | {{abbr|N/A|not applicable}} | {{abbr|N/A|not applicable}} | Pseudogene in humans – {{abbr|N/A|not applicable}} | {{abbr|N/A|not applicable}} | [14][18]
[14] |
|---|
| TAAR4 | TA2 | N/A | N/A | Pseudogene in humans – N/A | N/A | [14][18]
[14] |
|---|
| hTAAR5 | PNR | {{nowrap|Gs}}, {{nowrap|Golf}},
{{nowrap|Gq}}, {{nowrap|G12/13}} | CNS: brain (restricted),
spinal cord
Periphery: olfactory epithelium, intestines, testes, leukocytes | {{bull}}Olfaction: chemoreceptor for volatile & foul odorants | {{bull}}Agonists: trimethylamine, N,N-DMEA
{{bull}}Inverse agonists: 3-iodothyronamine | [8][18]
[14][19]
[20][21]
[22] |
|---|
| hTAAR6 | TA4
TAR4 | {{nowrap|Golf}}, other G protein coupling unknown | CNS: brain
Periphery: olfactory epithelium, intestines, testes, leukocytes, kidneys | {{bull}}Olfaction: chemoreceptor for volatile odorants | | [8][18]
[14][23] |
|---|
| TAAR7 | – | N/A | N/A | Pseudogene in humans – N/A | N/A | [8][18]
[14] |
|---|
| hTAAR8 | TA5
GPR102 | {{nowrap|Golf}}, Gi/o | CNS: brain
Periphery: olfactory epithelium, stomach, intestines, heart, testes, leukocytes, kidneys, lungs, muscle, spleen | {{bull}}Olfaction: chemoreceptor for volatile odorants | | [8][18]
[14][24] |
|---|
hTAAR9
{{#tag:ref|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.[25][18]|group="note" | TA3
TAR3 | {{nowrap|Golf}}, other G protein coupling unknown | CNS: spinal cord
Periphery: olfactory epithelium, intestines, leukocytes, pituitary gland, skeletal muscle, spleen | {{bull}}Olfaction: chemoreceptor for volatile odorants | | [8][18]
[14][26] |
|---|
- Notes
1. ^{{cite journal |vauthors=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 |title=Trace amines: identification of a family of mammalian G protein-coupled receptors |journal=PNAS |volume=98 |issue=16 |pages=8966–71 |year=2001 |pmid=11459929 |doi=10.1073/pnas.151105198 |pmc=55357}}
2. ^{{cite journal |vauthors=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 |title=Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor |journal=Mol. Pharmacol. |volume=60 |issue=6 |pages=1181–8 |year=2001 |pmid=11723224 |doi=10.1124/mol.60.6.1181}}
3. ^{{cite journal | vauthors = Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A | title = In-vivo pharmacology of Trace-Amine Associated Receptor 1 | journal = Eur. J. Pharmacol. | volume = 763| issue = | pages = 136–42| date = June 2015 | pmid = 26093041 | doi = 10.1016/j.ejphar.2015.06.026 }}
4. ^1 {{cite journal |vauthors=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 |title=3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone |journal=Nat. Med. |volume=10 |issue=6 |pages=638–42 |year=2004 |pmid=15146179 |doi=10.1038/nm1051}}
5. ^{{cite journal |vauthors=Lindemann L, Hoener MC |title=A renaissance in trace amines inspired by a novel GPCR family |journal=Trends Pharmacol. Sci. |volume=26 |issue=5 |pages=274–81 |year=2005 |pmid=15860375 |doi=10.1016/j.tips.2005.03.007}}
6. ^{{cite journal |vauthors=Hart ME, Suchland KL, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS |title=Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues |journal=J. Med. Chem. |volume=49 |issue=3 |pages=1101–12 |year=2006 |pmid=16451074 |doi=10.1021/jm0505718}}
7. ^{{cite journal |author=Grandy DK |title=Trace amine-associated receptor 1-Family archetype or iconoclast? |journal=Pharmacol. Ther. |volume=116 |issue=3 |pages=355–390 |year=2007 |pmid=17888514 |doi=10.1016/j.pharmthera.2007.06.007 |pmc=2767338}}
8. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 {{cite journal | vauthors = Liberles SD | title = Trace amine-associated receptors: ligands, neural circuits, and behaviors | journal = Curr. Opin. Neurobiol. | volume = 34 | issue = | pages = 1–7 | date = October 2015 | pmid = 25616211 | doi = 10.1016/j.conb.2015.01.001 | quote = 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.| pmc = 4508243 }}
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508243/figure/F2/ Figure 2: Table of ligands, expression patterns, and species-specific behavioral responses for each TAAR]
9. ^{{cite journal |doi=10.1073/pnas.0803229106 |vauthors=Hussain A, Saraiva LR, Korsching SI|title=Positive Darwinian selection and the birth of an olfactory receptor clade in teleosts|journal=PNAS |volume=106 |issue=11 |pages=4313–8 |year=2009 |pmid=19237578 |pmc=2657432 }}
10. ^{{cite journal | vauthors = Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP | title = International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature | journal = Pharmacol. Rev. | volume = 61 | issue = 1 | pages = 1–8 |date=March 2009 | pmid = 19325074 | pmc = 2830119 | doi = 10.1124/pr.109.001107 | url = | issn = }}
11. ^1 {{cite journal | vauthors = Liberles SD, Buck LB | title = A second class of chemosensory receptors in the olfactory epithelium | journal = Nature | volume = 442 | issue = 7103 | pages = 645–650 | date = August 2006 | pmid = 16878137 | doi = 10.1038/nature05066 }}
12. ^1 {{cite journal | author = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = J. Neurochem. | volume = 116 | issue = 2 | pages = 164–176 |date=January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}
13. ^1 2 {{cite journal | vauthors = Wallrabenstein I, Singer M, Panten J, Hatt H, Gisselmann G | title = Timberol® Inhibits TAAR5-Mediated Responses to Trimethylamine and Influences the Olfactory Threshold in Humans | journal = PLOS One | volume = 10 | issue = 12 | pages = e0144704 | date = 2015 | pmid = 26684881 | pmc = 4684214 | doi = 10.1371/journal.pone.0144704 | quote = 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.}}
14. ^1 2 3 4 5 6 7 8 9 10 {{cite web|title=Trace amine receptor: Introduction|url=http://www.iuphar-db.org/DATABASE/FamilyIntroductionForward?familyId=64|publisher=International Union of Basic and Clinical Pharmacology|accessdate=15 February 2014 | quote = 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.}}
15. ^1 {{cite journal |vauthors=Babusyte A, Kotthoff M, Fiedler J, Krautwurst D |title=Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2 |journal=J. Leukoc. Biol. |volume=93 |issue=3 |pages=387–94 |date=March 2013 |pmid=23315425 |doi=10.1189/jlb.0912433 |url=}}
16. ^1 {{cite web|title=TAAR2|url=http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=167|publisher=International Union of Basic and Clinical Pharmacology|accessdate=15 May 2018 | quote = Primary Transduction Mechanisms
Comments: TAAR2 is found to be coexpressed with Gα proteins. However, the transduction pathway of TAAR2 is yet to be determined.}}
17. ^1 {{cite journal | vauthors = Khan MZ, Nawaz W | title = The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system | journal = Biomed. Pharmacother. | volume = 83 | issue = | pages = 439–449 | date = October 2016 | pmid = 27424325 | doi = 10.1016/j.biopha.2016.07.002 | quote = }}
18. ^1 2 3 4 5 6 7 8 9 10 11 12 13 {{cite journal | vauthors = Berry MD, Gainetdinov RR, Hoener MC, Shahid M | title = Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges | journal = Pharmacology & Therapeutics | volume = 180 | issue = | pages = 161–180 | date = December 2017 | pmid = 28723415 | doi = 10.1016/j.pharmthera.2017.07.002 | quote = }}
19. ^{{cite book|last=Offermanns|first=Stefan|title=Encyclopedia of Molecular Pharmacology | year=2008 | publisher=Springer | location=Berlin | isbn=3540389164 | pages=1219–1222 | edition=2nd | editor = Walter Rosenthal}}
20. ^{{cite journal |vauthors=Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, Becker C, Schmidt A, Hatt H, Hummel T, Gisselmann G |title=Human trace amine-associated receptor TAAR5 can be activated by trimethylamine |journal=PLOS ONE |volume=8 |issue=2 |pages=e54950 |year=2013 |pmid=23393561 |pmc=3564852 |doi=10.1371/journal.pone.0054950 |url=}}
21. ^{{cite journal | vauthors = Zhang J, Pacifico R, Cawley D, Feinstein P, Bozza T | title = Ultrasensitive detection of amines by a trace amine-associated receptor | journal = J. Neurosci. | volume = 33 | issue = 7 | pages = 3228–39 |date=February 2013 | pmid = 23407976 | pmc = 3711460 | doi = 10.1523/JNEUROSCI.4299-12.2013 | quote = 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).}}
22. ^{{cite journal | vauthors = 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 | title = Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5 | journal = PLOS ONE | volume = 10 | issue = 2 | pages = e0117774 | year = 2015 | pmid = 25706283 | doi = 10.1371/journal.pone.0117774 | pmc=4382497}}
23. ^{{cite web|title=TAAR6|url=http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=171|publisher=International Union of Basic and Clinical Pharmacology|accessdate=15 May 2018 | quote = 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}}
24. ^{{cite journal | vauthors = 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 | title = Analysis of human TAAR8 and murine Taar8b mediated signaling pathways and expression profile | journal = Int J Mol Sci | volume = 15 | issue = 11 | pages = 20638–55 | year = 2014 | pmid = 25391046 | pmc = 4264187 | doi = 10.3390/ijms151120638 | url = }}
25. ^1 2 3 4 {{cite journal | vauthors = Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR, Pin JP, Spedding M, Harmar AJ | title = International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands | journal = Pharmacol. Rev. | volume = 65 | issue = 3 | pages = 967–86 |date=July 2013 | pmid = 23686350 | pmc = 3698937 | doi = 10.1124/pr.112.007179 | quote =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).}}
26. ^{{cite web|title=TAAR9|url=http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=173|publisher=International Union of Basic and Clinical Pharmacology|accessdate=15 May 2018 | quote = 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].}}
| Disease links and clinical significance{{expand section|with=coverage of relevant material from this review[18]|date=March 2018}} See also - Olfactory receptor
- Odorant
- Pheromone
- Pheromone receptor
- Psychostimulant
- Thyronamine
- Trace amine
References {{Reflist|30em}} External links - {{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1355 | title = Trace Amine Receptors | accessdate = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | archiveurl = | archivedate = }}
{{TAAR ligands|state=expanded}}{{G protein-coupled receptors}} 1 : G protein-coupled receptors |