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^[1]^[2]。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^[3]^[4]^[5]^[6]^[7]^[8]。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^[5]。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^[9]。

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^[10]^[11]。

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。

さらに見る サブタイプ, 以前の名称 ...

ヒトのTAARの薬理学的・分子生物学的性質
サブタイプ	以前の名称	シグナル伝達	発現プロファイル	ヒトにおける既知もしくは推定される機能^{[note 1]}	既知のリガンド	文献
TAAR1（英語版）	TA₁ TAR1	G_s、G_q、GIRK、 β-アレスチン2（英語版）	CNS: 脳（広範）、脊髄末梢: 膵β細胞、胃、十二指腸、腸、白血球、その他^{[note 2]}	• CNS: モノアミン/グルタミン酸神経伝達の調節 • CNS: 認知過程、気分状態の調節 • 末梢: 白血球の走化性 • 末梢: 消化管ホルモン（英語版）放出と血糖値の調節 • 満腹感と体重の調節	• 微量アミン（チラミン、フェネチルアミン、N-メチルフェネチルアミン（英語版）など） • モノアミン神経伝達物質（ドーパミンなど） • アンフェタミンと一部の構造的アナログ	^[3]^[12] ^[14]^[15]
TAAR2（英語版） ^{[note 3]}	GPR58	G_olf（英語版）、その他不明な共役Gタンパク質^{[note 4]}	CNS: 脳（限定的）^{[note 5]} 末梢: 嗅上皮（英語版）、腸、心臓、精巣、白血球	• 末梢: 白血球の走化性 • 嗅覚: 揮発性匂い物質に対する化学受容体^{[note 6]}		^[9]^[12] ^[14]^[15] ^[17]^[18]
TAAR3	GPR57	N/A	N/A	ヒトでは偽遺伝子 – N/A	N/A	^[16]^[12] ^[14]
TAAR4	TA₂	N/A	N/A	ヒトでは偽遺伝子 – N/A	N/A	^[16]^[12] ^[14]
TAAR5（英語版）	PNR	G_s、 G_olf、G_q、G_12/13	CNS: 脳（限定的）、脊髄末梢: 嗅上皮、腸、精巣、白血球	• 嗅覚: 揮発性不快臭に対する化学受容体^{[note 6]}	• アゴニスト: トリメチルアミン、N,N-ジメチルエチルアミン • インバースアゴニスト: 3-ヨードチロナミン（英語版）	^[9]^[12] ^[14]^[20] ^[21]^[22] ^[23]
TAAR6（英語版）	TA₄ TAR4	G_olf、その他不明な共役Gタンパク質	CNS: 脳末梢: 嗅上皮、腸、精巣、白血球、腎臓	• 嗅覚: 揮発性匂い物質に対する化学受容体^{[note 6]}	• アゴニスト: プトレシン、カダベリン^[24]	^[9]^[12] ^[14]^[25]
TAAR7	–	N/A	N/A	ヒトでは偽遺伝子 – N/A	N/A	^[9]^[12] ^[14]
TAAR8（英語版）	TA₅ GPR102	G_olf、G_i/o	CNS: 脳末梢: 嗅上皮、メラノサイト^[26]、胃、腸、心臓、精巣、白血球、腎臓、肺、筋肉、脾臓	• 嗅覚: 揮発性匂い物質に対する化学受容体^{[note 6]}	• アゴニスト: プトレシン、カダベリン^[24]	^[9]^[12] ^[14]^[27]
TAAR9（英語版） ^{[note 7]}	TA₃ TAR3	G_olf、その他不明な共役Gタンパク質	CNS: 脊髄末梢: 嗅上皮、腸、白血球、下垂体、骨格筋、脾臓	• 嗅覚: 揮発性匂い物質に対する化学受容体^{[note 6]}	• アゴニスト: N-メチルピペリジン（N-methyl piperidine、CAS: 626-67-5）^[28]	^[9]^[12] ^[14]^[29]
Notes [N 1] 2017年12月時点では、TAAR2、TAAR5、TAAR6、TAAR8、TAAR9の嗅上皮以外の末梢組織、中枢神経系における機能は明らかにされていない^[12]。 [N 2] TAAR1は嗅上皮に発現していない唯一のTAARである^[9]^[13]。したがって、他のTAARのように嗅覚受容体として機能しているわけではない^[9]^[13]。 [N 3] TAAR2はアジア人の10–15%では、上流の終止コドン形成と関係したSNPのため機能的な受容体とはならない^[16]^[12]。 [N 4] TAAR2はGαタンパク質と共発現していることが明らかにされているが、正確なシグナル伝達機構が確立されているわけではない^[12]^[17]。 [N 5] TAAR2の発現は小脳で観察されている^[18]。 [N 6] ヒトやその他の動物では、嗅上皮に発現しているTAARは揮発性のアミン系の匂い物質（特定種のフェロモンなどを含む）を検知する嗅覚受容体として機能する^[9]^[14]。これらのTAARはフェロモン受容体の一部として機能していると推定されている^[9]^[14]。ヒト以外の動物での研究に関する総説では、嗅上皮のTAARがアゴニストに対する誘引・忌避行動を媒介している場合があることが指摘されている^[9]。この総説では、TAARを介して引き起こされる行動応答が種によって異なる場合があることも指摘されている^[9]。一例としてTAAR5は、トリメチルアミンに対するマウスの誘引行動、ラットの忌避行動を媒介している^[9]。ヒトでもTAAR5はトリメチルアミンに対する忌避を媒介していると考えられている。トリメチルアミンはヒトTAAR5のアゴニストであり、ヒトの嫌がる魚のような悪臭を有する^[9]^[19]。一方、TAAR5はヒトにおけるトリメチルアミンの嗅覚検知を担う唯一の嗅覚受容体であるわけではない^[9]^[19]。2015年12月時点で公表されている研究では、ヒトTAAR5を介したトリメチルアミンに対する忌避行動が実験的に示されているわけではない^[19]。 [N 7] 大部分の人ではTAARは機能的受容体であるが、10–30%の人では上流終止コドン形成を伴う多型による機能喪失が生じている^[16]^[12]。

閉じる

臨床的意義

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^[30]^[31]^[32]。

[1]
“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.
[2]
“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.
[3]
“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.
[4]
“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.
[5]
“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.
[6]
“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.
[7]
“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.
[8]
“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.
[9]
“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. "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]
“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.
[11]
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.
[12]
“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.
[13]
“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.
[14]
“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.”
[15]
“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.
[16]
“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. "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)."
[17]
“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.”
[18]
“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.
[19]
“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. "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]
“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.
[22]
“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. "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]
“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.
[24]
“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.
[25]
“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”
[26]
“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.
[27]
“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.
[28]
“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.
[29]
“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].”
[30]
“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.
[31]
“Sunovion: creating therapies to help transform people's lives”. www.sunovion.com. 2022年6月4日閲覧。
[32]
“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。

[13] [N 1]
2017年12月時点では、TAAR2、TAAR5、TAAR6、TAAR8、TAAR9の嗅上皮以外の末梢組織、中枢神経系における機能は明らかにされていない^[12]。

[15] [N 2]
TAAR1は嗅上皮に発現していない唯一のTAARである^[9]^[13]。したがって、他のTAARのように嗅覚受容体として機能しているわけではない^[9]^[13]。

[19] [N 3]
TAAR2はアジア人の10–15%では、上流の終止コドン形成と関係したSNPのため機能的な受容体とはならない^[16]^[12]。

[21] [N 4]
TAAR2はGαタンパク質と共発現していることが明らかにされているが、正確なシグナル伝達機構が確立されているわけではない^[12]^[17]。

[23] [N 5]
TAAR2の発現は小脳で観察されている^[18]。

[pheromone-25] [N 6]
ヒトやその他の動物では、嗅上皮に発現しているTAARは揮発性のアミン系の匂い物質（特定種のフェロモンなどを含む）を検知する嗅覚受容体として機能する^[9]^[14]。これらのTAARはフェロモン受容体の一部として機能していると推定されている^[9]^[14]。ヒト以外の動物での研究に関する総説では、嗅上皮のTAARがアゴニストに対する誘引・忌避行動を媒介している場合があることが指摘されている^[9]。この総説では、TAARを介して引き起こされる行動応答が種によって異なる場合があることも指摘されている^[9]。一例としてTAAR5は、トリメチルアミンに対するマウスの誘引行動、ラットの忌避行動を媒介している^[9]。ヒトでもTAAR5はトリメチルアミンに対する忌避を媒介していると考えられている。トリメチルアミンはヒトTAAR5のアゴニストであり、ヒトの嫌がる魚のような悪臭を有する^[9]^[19]。一方、TAAR5はヒトにおけるトリメチルアミンの嗅覚検知を担う唯一の嗅覚受容体であるわけではない^[9]^[19]。2015年12月時点で公表されている研究では、ヒトTAAR5を介したトリメチルアミンに対する忌避行動が実験的に示されているわけではない^[19]。

[34] [N 7]
大部分の人ではTAARは機能的受容体であるが、10–30%の人では上流終止コドン形成を伴う多型による機能喪失が生じている^[16]^[12]。

[pmid11459929-1] [1]
“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.

[pmid11723224-2] [2]
“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.

[Miller-3] [3]
“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.

[In-vivo_TAAR1-4] [4]
“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.

[pmid15146179-5] [5]
“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.

[pmid15860375-6] [6]
“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.

[pmid16451074-7] [7]
“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.

[pmid17888514-8] [8]
“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.

[TAAR_2015_review_-_olfactory_TAARs-9] [9]
“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. "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

[pmid19237578-10] [10]
“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.

[11] [11]
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.

[Berry_hTAAR_pharmacology_December_2017_review-12] [12]
“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.

[Liberles_2006-14] [13]
“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.

[IUPHAR_TAAR-16] [14]
“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.”

[pmid23315425-17] [15]
“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.

[IUPHAR_update-18] [16]
“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. "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)."

[IUPHAR_TAAR2-20] [17]
“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.”

[Human_trace_amines_and_hTAARs_October_2016_review-22] [18]
“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.

[hTAAR5_and_trimethylamine_aversion-24] [19]
“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. "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."

[Molecular_Pharm-26] [20]
Offermanns, Stefan (2008). Walter Rosenthal. ed. Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222. ISBN 978-3540389163

[pmid23393561-27] [21]
“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.

[hTAAR5_ligands-28] [22]
“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. "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)."

[hTAAR5_inverse_agonist-29] [23]
“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.

[pmid29324768-30] [24]
“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.

[IUPHAR_TAAR6-31] [25]
“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”

[32] [26]
“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.

[Gi/o-33] [27]
“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.

[pmid25616211-35] [28]
“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.

[IUPHAR_TAAR9-36] [29]
“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].”

[:0-37] [30]
“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.

[:1-38] [31]
“Sunovion: creating therapies to help transform people's lives”. www.sunovion.com. 2022年6月4日閲覧。

[:2-39] [32]
“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。

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[note 1]

[note 2]

[12]

[14]

[15]

[note 3]

[note 4]

[note 5]

[note 6]

[17]

[18]

[16]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[note 7]

[28]

[29]

[13]

[19]

[30]

[31]

[32]

微量アミン関連受容体

臨床的意義

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微量アミン関連受容体

臨床的意義

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動物のTAAR

ヒトのTAAR

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