微量アミン関連受容体

微量アミン関連受容体（びりょうアミンかんれんじゅようたい、英: trace amine-associated receptor、TAAR、微量アミンレセプター（TA、TAR）と呼ばれることもある）は、2001年に発見されたGタンパク質共役受容体のグループである。ヒトには6種類存在する機能的なTAARの1つであるTAAR1（英語版）は、フェネチルアミン、チラミン、トリプタミン（それぞれフェニルアラニン、チロシン、トリプトファンの代謝産物である）、エフェドリン、そしてアンフェタミン、メタンフェタミン、メチレンジオキシメタンフェタミン（MDMA）といった合成精神刺激薬などの微量アミン（英語版）に対する内在性受容体としての役割のため、学術研究や医薬品開発において大きな関心が寄せられている。2004年、哺乳類のTAAR1は甲状腺ホルモンの脱炭酸・脱ヨード化類縁体であるチロナミンの受容体であることも示された。脊椎動物では、TAAR2からTAAR9は揮発性のアミン系の匂い物質に対する嗅覚受容体として機能する。 さまざまな動物のゲノムに含まれているTAAR遺伝子・偽遺伝子の数を下に示す。 ヒト – 6遺伝子（TAAR1（英語版）、TAAR2（英語版）、TAAR5（英語版）、TAAR6（英語版）、TAAR8（英語版）、TAAR9（英語版））と3偽遺伝子（TAAR3（英語版）、TAAR4P、TAAR7P） マウス – 15遺伝子、1偽遺伝子 ラット – 17遺伝子、2偽遺伝子 ゼブラフィッシュ – 112遺伝子、4偽遺伝子 ネッタイツメガエル – 3遺伝子、0偽遺伝子 メダカ – 25遺伝子、1偽遺伝子 イトヨ – 25遺伝子、1偽遺伝子 ヒトでは6種類のTAAR（TAAR1、TAAR2、TAAR5、TAAR6、TAAR8、TAAR9）が同定され、部分的に特性解析が行われている。下の図は総説や薬理学関連データベースのほか、発現プロファイル、シグナル伝達機構、リガンド、生理学的機能に関する一次資料からの情報をまとめたものである。 ウロタロント（英語版）/SEP-363856は、統合失調症に対する第3相臨床試験、パーキンソン病における精神症状に対する初期段階の試験が行われているTAAR1アゴニストである。この薬剤はFDAによる「画期的治療薬」指定を受けている。 ^ “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). doi:10.1073/pnas.151105198. PMC 55357. PMID 11459929. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC55357/.  ^ “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). doi:10.1124/mol.60.6.1181. PMID 11723224.  ^ a b “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). doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005101/.  ^ “In-vivo pharmacology of Trace-Amine Associated Receptor 1”. European Journal of Pharmacology 763 (Pt B): 136–142. (September 2015). doi:10.1016/j.ejphar.2015.06.026. PMID 26093041.  ^ a b “3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone”. Nature Medicine 10 (6): 638–642. (June 2004). doi:10.1038/nm1051. PMID 15146179.  ^ “A renaissance in trace amines inspired by a novel GPCR family”. Trends in Pharmacological Sciences 26 (5): 274–281. (May 2005). doi:10.1016/j.tips.2005.03.007. PMID 15860375.  ^ “Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues”. Journal of Medicinal Chemistry 49 (3): 1101–1112. (February 2006). doi:10.1021/jm0505718. PMID 16451074.  ^ “Trace amine-associated receptor 1-Family archetype or iconoclast?”. Pharmacology & Therapeutics 116 (3): 355–390. (December 2007). doi:10.1016/j.pharmthera.2007.06.007. PMC 2767338. PMID 17888514. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767338/.  ^ a b c d e f g h i j k l m n o p “Trace amine-associated receptors: ligands, neural circuits, and behaviors”. Current Opinion in Neurobiology 34: 1–7. (October 2015). doi:10.1016/j.conb.2015.01.001. PMC 4508243. PMID 25616211. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508243/. "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 ^ “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). Bibcode: 2009PNAS..106.4313H. doi:10.1073/pnas.0803229106. PMC 2657432. PMID 19237578. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657432/.  ^ Davenport, Anthony P.; Alexander, Stephen P. H.; Sharman, Joanna L.; Pawson, Adam J.; Benson, Helen E.; Monaghan, Amy E.; Liew, Wen Chiy; Mpamhanga, Chidochangu P. et al. (2013-07). “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. ISSN 1521-0081. PMC 3698937. PMID 23686350. https://pubmed.ncbi.nlm.nih.gov/23686350.  ^ a b c d e f g h i j k l m n “Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges”. Pharmacology & Therapeutics 180: 161–180. (December 2017). doi:10.1016/j.pharmthera.2017.07.002. PMID 28723415.  ^ a b “A second class of chemosensory receptors in the olfactory epithelium”. Nature 442 (7103): 645–650. (August 2006). Bibcode: 2006Natur.442..645L. doi:10.1038/nature05066. PMID 16878137.  ^ a b c d e f g h i j k “Trace amine receptor: Introduction”. International Union of Basic and Clinical Pharmacology. 15 February 2014閲覧。 “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.” ^ a b “Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2”. Journal of Leukocyte Biology 93 (3): 387–394. (March 2013). doi:10.1189/jlb.0912433. PMID 23315425.  ^ a b c d “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. (July 2013). doi:10.1124/pr.112.007179. PMC 3698937. PMID 23686350. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698937/. "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)."  ^ a b “TAAR2”. International Union of Basic and Clinical Pharmacology. 15 May 2018閲覧。 “Primary Transduction Mechanisms Comments: TAAR2 is found to be coexpressed with Gα proteins. However, the transduction pathway of TAAR2 is yet to be determined.” ^ a b “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). doi:10.1016/j.biopha.2016.07.002. PMID 27424325.  ^ a b c “Timberol® Inhibits TAAR5-Mediated Responses to Trimethylamine and Influences the Olfactory Threshold in Humans”. PLOS ONE 10 (12): e0144704. (2015). Bibcode: 2015PLoSO..1044704W. doi:10.1371/journal.pone.0144704. PMC 4684214. PMID 26684881. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684214/. "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."  ^ Offermanns, Stefan (2008). Walter Rosenthal. ed. Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222. ISBN 978-3540389163. https://archive.org/details/encyclopediamole12rose  ^ “Human trace amine-associated receptor TAAR5 can be activated by trimethylamine”. PLOS ONE 8 (2): e54950. (2013). Bibcode: 2013PLoSO...854950W. doi:10.1371/journal.pone.0054950. PMC 3564852. PMID 23393561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564852/.  ^ “Ultrasensitive detection of amines by a trace amine-associated receptor”. The Journal of Neuroscience 33 (7): 3228–3239. (February 2013). doi:10.1523/JNEUROSCI.4299-12.2013. PMC 3711460. PMID 23407976. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711460/. "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)."  ^ “Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5”. PLOS ONE 10 (2): e0117774. (2015). Bibcode: 2015PLoSO..1017774D. doi:10.1371/journal.pone.0117774. PMC 4382497. PMID 25706283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382497/.  ^ a b “Identifying human diamine sensors for death related putrescine and cadaverine molecules”. PLOS Computational Biology 14 (1): e1005945. (January 2018). Bibcode: 2018PLSCB..14E5945I. doi:10.1371/journal.pcbi.1005945. PMC 5783396. PMID 29324768. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783396/.  ^ “TAAR6”. International Union of Basic and Clinical Pharmacology. 15 May 2018閲覧。 “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” ^ “Deregulation of Trace Amine-Associated Receptors (TAAR) Expression and Signaling Mode in Melanoma”. Biomolecules 12 (1): 114. (January 2022). doi:10.3390/biom12010114. PMC 8774021. PMID 35053262. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774021/.  ^ “Analysis of human TAAR8 and murine Taar8b mediated signaling pathways and expression profile”. International Journal of Molecular Sciences 15 (11): 20638–20655. (November 2014). doi:10.3390/ijms151120638. PMC 4264187. PMID 25391046. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264187/.  ^ “Trace amine-associated receptors: ligands, neural circuits, and behaviors”. Current Opinion in Neurobiology 34: 1–7. (October 2015). doi:10.1016/j.conb.2015.01.001. PMC 4508243. PMID 25616211. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508243/.  ^ “TAAR9”. International Union of Basic and Clinical Pharmacology. 15 May 2018閲覧。 “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].” ^ “Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia”. ACS Medicinal Chemistry Letters 13 (1): 92–98. (January 2022). doi:10.1021/acsmedchemlett.1c00527. PMC 8762745. PMID 35047111. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762745/.  ^ “Sunovion: creating therapies to help transform people's lives”. www.sunovion.com. 2022年6月4日閲覧。 ^ “Sunovion and PsychoGenics Announce that SEP-363856 Has Received FDA Breakthrough Therapy Designation for the Treatment of People with Schizophrenia” (英語). news.sunovion.com. 2022年6月4日閲覧。 嗅覚受容体 芳香化合物 フェロモン 精神刺激薬 チロナミン 微量アミン（英語版）