General

Trace amines, such as para-tyramine, β-phenylethylamine (β-PEA) and octopamine were discovered over a century ago (e.g. β-PEA - Nencki, 1876; reviewed in [27]) and are well known sympathomimetics [5,17]. In mammals they are synthesised from aromatic amino acids [8,11,19] at rates comparable to classical monoamines but detectable only at trace levels as they are substrates for MAO and have a half life of around 30 seconds [22,44]. Trace amines are also present in beer, wine, cheese and chocolate in significant amounts [13,28]. In insects, tyramine and octopamine are well-characterised neurotransmitters, acting via their own GPCRs to modulate metabolism and muscle tone [2,51].

In 2001, a novel mammalian GPCR was cloned in a search for further subtypes of 5-HT receptor and was shown to have high affinity (nanomolar) for trace amines, hence named the trace amine 1 (TA₁) receptor [7]. Subsequently, a family of genes encoding trace amine receptors were cloned [7,35] that showed closest homology to the aminergic receptors, (5-HT, adrenergic, dopaminergic and histaminergic). The gene name was initially abbreviated to TA and TAR, following the initial pairing. However, not all have high affinity for trace amines, which has led to the adoption of the nomenclature of 'trace amine associated receptors' (TAARs) [35].

Analysis has shown that in man there are 6 functional TAAR genes (see table 1). So far only TA₁ has been well characterised and is the focus of this commentary. The gene encoding this receptor has been designated TAAR1 by HUGO. Since trace amines have been identified as the endogenous ligands for the receptor it has been classified as the trace amine 1 (TA₁) receptor [7]. In 2006 it was shown that the rat TA₁ receptor expressed in HEK293 cells was also activated by thyronamines (decarboxylated and deiodinated metabolites of the thyroid hormones) [29,52] with a similar potency to tyramine [12]. Cardiac effects of iodothyronamines have been reported in rat but the rank orders of potencies and ligand binding led the authors to suggest iodothyronamines may be acting at a different trace amine associated receptor [24].

Receptor Structure

The human TA₁ receptor is a member of the rhodopsin-type superfamily (i.e. a class A GPCR), with 339 amino acids. It has a predicted seven transmembrane spanning domain structure with short N- and C-terminal domains of 23-49 and 27-33 amino acids respectively [35]. Rat and mouse TA₁ both have 332 amino acids, with sequence identities of 78% and 75% in relation to man respectively. Lower potency of tyramine and 3-iodothyronamine for the mouse receptor compared to the rat receptor has been attributed in part to a difference in residue 4.56 in transmembrane 4 whereas preference for the β-phenyl ring is directed by residue 7.39 in transmembrane 7 [58]. In mouse and rat TA₁ receptors, residues important in binding amphetamine and methamphetamine in vitro are suggested to be 102 (3.32) and 268 (6.55) whereas residue 287 (7.39) was important for determining species stereoselectivity [47]. Cichero and colleagues [15] have derived a homology model for the human TA₁ and together with docking studies using RO5166017, β-phenylethylamine and 3-iodothyronamine used these data to propose key residues, D103 and N286, involved in ligand recognition.

Receptor Signalling

TA₁ is known to couple to G_s in vitro, as tyramine causes intracellular cAMP accumulation in COS-7 [7] and HEK293 [35] cells expressing human TA₁. TA₁ has been coupled via the promiscuous G_q protein, G_α16, in CHO [12] and RD-HGA16 [32-33] cells to mobilization of intracellular calcium. Associated in vivo receptor signal transduction mechanisms have not been identified.

Physiology

Studies using PR-PCR and in situ hybridization have shown that mRNA encoding TA₁ is widely distributed throughout the central nervous system and some peripheral tissues [7,14,16,41,48,64-65]. This includes components of the limbic system, eg. amygdala, and areas rich in monoaminergic cell bodies, e.g. dorsal raphé nucleus and ventral tegmental area (VTA). TA₁ has been shown to inhibit uptake and induce efflux of classical monoamines in murine striatal and thalamic synaptosomes [62,65] suggesting that TA₁ has a role in modulating monoaminergic neuronal activity [37]. Electrophysiological studies have demonstrated that TA₁ activation inhibited spontaneous firing of dopaminergic neurones in the VTA [9,37,49-50]. TA₁ may also be immunomodulatory as mRNA for the receptor has been found in circulating leukocytes and is upregulated following administration of phytohaemagglutinin [3,16,41].

Effects of Gene Deletion

A TA₁ knock out mouse has been developed and is viable [61-62,65]. Deletion of the gene for the receptor has psychomotor effects and has been proposed separately as an animal model of schizophrenia [61] and hemi-Parkinsonism [55]. Trace amines and their receptors may therefore be useful in treating various neurological and psychiatric disorders [6,10] and are potentially druggable targets [18]. Gene deletion has been implicated in augmentation of biochemical, electrophysiological and behavioural responses to amphetamine, metamphetamine and 3,4-methylenedioxymetamphetmaine [1,20,61] indicating that targeting TA1 may be a novel strategy in amphetamine-related conditions [54]. The effect of knockout of the endogenous agonists tyramine and β-PEA has not been assessed, although as these compounds are also metabolites, they cannot readily be knocked-out without identifying enzymes exclusive to their production.

Polymorphisms of the gene encoding human TA₁ have not yet been reported.

Pharmacology

Endogenous TA₁ agonists include p-tyramine and phenylethylamine [4,7,12,46,60-61]. Additionally, the thyroid hormone derived 3-iodothyronamine (T₁AM) activates TA₁ but also other TAARs [52]. Radiolabelled tyramine ([³H]tyramine, e.g. [7] and T₁AM (eg. [¹²⁵I]-, [²H]-, [³H]-T₁AM [40]) ligands are available.

Exogenous agonists include amphetamine and derivatives, including methamphetamine and MDMA, with some species dependent stereoselectivity [12,46].

Lead antagonists [9,56-57] and partial agonists [25,50] of the TA₁ receptor have been rationally synthesised and are being pharmacologically characterised. For comprehensive reviews of the TA₁ receptor see [18,27,31,36,38-39,45,54,63,66].

Nomenclature

A number of different nomenclatures have previously been proposed for both the receptor proteins and the family of genes encoding the trace amine and trace amine associated receptors. In order to facilitate comparison between members of this family, these are given in Table 1. To date only one receptor TA₁, has been paired with its cognate ligand and repeated by a number of different groups, leading to official nomenclature. The unofficial receptor names for the remaining receptors are included for comparison and are awaiting clear identification of their endogenous ligands, together with the official gene names.

TABLE 1 Summary of human, mouse and rat genes encoding trace amine and trace amine associated receptors.

Receptor		Human gene			Mouse gene		Rat gene		Notes
IUPHAR Receptor Nomenclature		Old Name	New Name	Swiss-Prot/RefSeq	Name	Swiss-Prot/RefSeq	Name	Swiss-Prot/RefSeq
TA1		TAR1	TAAR1	Q96RJ0 NP_612200	Taar1	Q923Y8 NP_444435	Taar1	Q923Y9 NP_599155
Unofficial Receptor Terminology*
TA2		-	-	-	Taar4	Q5QD15 NP_001008499	Taar4	Q923Y7 NP_783173
TA3		TAR3	TAAR9	Q96R19 NP_778227	Taar9	Q5QD04 NP_001010831	Taar9	Q923Y6 NP_783192	1
TA4		TAR4	TAAR6	Q96R18 NP_778237	Taar6	Q5QD13 NP_001010828	Taar6	Q923Y5 NP_783174	2
TA5		GPR102	TAAR8	Q969N4 NP_444508	-	-	-	-
TA6		-	-	-	-	-	Taar7h	Q923Y4 NP_783177
TA7		-	-	-	Taar8b	Q5QD06 NP_001010837	Taar8b	Q923Y3 NP_783191
TA8		-	-	-	Taar7a	Q5QD12 NP_001010829	Taar7a	Q923Y2 NP_783175
TA9		-	-	-	-	-	Taar7g	Q923Y1 NP_783178
TA10		-	-	-	Taar8c	Q5QD05 NP_001010840	Taar8c	Q923Y0 NP_783190
TA11		-	-	-	Taar8a	Q5QD07 NP_001010830	Taar8a	Q923X9 NP_783189
TA12		-	-	-	Taar7b	Q5QD11 NP_001010827	Taar7b	Q923X8 NP_783176
TA13		-	-	-	Taar7f	Q5QD08 NP_001010839	Taar7f	Pseudogene
TA14		-	-	-	Taar7e	Q5QD09 NP_001010835	Taar7e	Q923X6 NP_783180
TA15		-	-	-	Taar7d	Q5QD10 NP_001010838	Taar7d	Q923X5 NP_783181
GPR57		-	-	-	Taar3	Q5QD16 NP_001008429	-	-
GPR58		GPR58	TAAR2	Q9P1P5 NP_001028252 or NP_055441	Taar2	Q5QD17 NP_001007267	Taar2	NP_001008512
PNR		PNR	TAAR5	O14804 NP_003958	Taar5	Q5QD14 NP_001009574	Taar5	Q5QD23 NP_001009650
* Nomenclature as designated by [7]. See Lindemann and Hoener [36] for further information on TAARs and Foord et al. [23] and Schöneberg et al. [53] for further information on pseudogenes. NOTES Stop codon present in 10% of humans. Polymorphisms in the human gene have been reported to be associated with schizophrenia and bipolar disorder [21,42-43].

TA₁

In Table 1, the International Union of Pharmacology recommended nomenclature for the receptor protein encoded by the gene TAAR1 as trace amine receptor 1, abbreviated to TA₁, first proposed by [7]. This follows the agreed convention on naming receptor proteins after the cognate endogenous ligand and there is no addition of an R to abbreviations for any receptor protein. See the IUPHAR recommendation for trace amine receptor nomenclature [38].

TAAR1 Gene

The Human Genome Organisation (HUGO) Gene Nomenclature Committee has approved the gene symbol for the trace amine receptor 1 as TAAR1 (see HUGO). The rat and mouse genes follow the International Committee on Standardized Genetic Nomenclature for Mice and Rat Genome and Nomenclature Committee to use lower case italics: Taar1. This distinguishes the human gene in capitals from rodents.

Other Family Members

In humans, a further five genes are predicted to exist encoding trace amine associated receptors, TAAR2, TAAR5, TAAR6, TAAR8 and TAAR9 (Table 1) and are thought to be functional genes. TAAR3 appears to be a pseudogene in some individuals but not others [26,59]. TAAR4 is a psuedogene in man and with TAAR3 occurs as functional gene in rats and mice. In addition, 9 further genes are present in rodents but not in man [35].

Odorants are detected in the nasal olfactory epithelium by the odorant receptor family, whose ~1,000 members allow the discrimination of many different of odorants. In a key paper, Liberles and Buck [34] reported the presence of trace amine-associated receptors that, like odorant receptors, are expressed in a unique subset of neurons dispersed in the the mouse olfactory epithelium. They expressed some of the mouse TAAR genes in HEK293 cells linked to a flourescent reporter and found several responded to various amine ligands.

(1) In agreement with previous reports for human and rat TA₁, mouse TA₁ receptor recognised β-phenylethylamine [34] with an EC₅₀ = 0.1 mM.

(2) Mouse Taar3 responded to several primary amines, including isoamylamine (EC₅₀ = 10 mM) and cyclohexylamine, but interestingly not to the corresponding alcohols, isoamylalcohol and cyclohexanol indicating slight variations in ligand structure eliminated ligand activity in some cases.

(3) Mouse Taar5 (an orthologue also exists in humans, Table 1) responded to tertiary amines trimethylamine (EC₅₀ = 0.3 mM) and N-methylpiperidine, but not to the related compounds methylamine, dimethylamine and tetramethylammonium chloride.

(4) Mouse Taar7f to responded to the tertiary amine, N-methylpiperidine (EC₅₀ = 20 mM)

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.

Human homologs of Taar3, Taar4, and Taar7 are thought to be pseudogenes but Taar5 does have an apparently functional human ortholog and the results suggest that functional members of the family more generally respond to trace amines. Responses were not reported for the other human orthologs TAAR2, TAAR6, TAAR8 and TAAR9 (or whether they were successfully expressed in HEK293 cells) and a role in man for these TAARs in man is not yet clear.

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. Hashiguchi and Nishida [30] carried out a careful phylogenetic analysis of the trace amine receptors in fish, amphibians, birds and mammals and concluded (from the species they considered) that there are five types of trace amine receptor. The first type included expanded 'trace amine-like' GPCR families within fish (fish can respond to catecholamines and their metabolites when they are introduced into their water). However, Type I also included the murine Taar receptors demonstrated to have an olfactory role and the human trace amine receptors, TAAR5, TAAR6 and TAAR8. Subfamily II also contained Taars, that, in the mouse, are expressed in the olfactory epithelium and function as receptors for volatile amines [34]. Subfamilies III and V had no mammalian members. Subfamily IV contained human and murine TAAR1 and Taar1 genes respectively. To date, these analyses suggest that TAAR1 gene alone encodes a trace amine receptor that may serve a non-sensory function. 'Trace amine pharmacology' probably extends beyond the putative trace amine receptors. It will require further characterization using pharmacology and physiology to determine whether the trace amine receptors are 'sensory' or not [27].

1. Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM. (2012) Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1. Pharmacol Biochem Behav, 101 (2): 201-7. [PMID:22079347]

2. Axelrod J, Saavedra JM. (1977) Octopamine. Nature, 265 (5594): 501-4. [PMID:13310]

3. Babusyte A, Kotthoff M, Fiedler J, Krautwurst D. (2013) Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2. J Leukoc Biol, 93 (3): 387-94. [PMID:23315425]

4. Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, Violin JD, Lefkowitz RJ, Caron MG, Gainetdinov RR. (2008) Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor. Mol Pharmacol, 74 (3): 585-594. [PMID:18524885]

5. Barger G, Dale HH. (1910) Chemical structure and sympathomimetic action of amines. J Physiol (Lond.), 41 (1-2): 19-59. [PMID:16993040]

6. Berry MD. (2007) The potential of trace amines and their receptors for treating neurological and psychiatric diseases. Rev Recent Clin Trials, 2 (1): 3-19. [PMID:18473983]

7. Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S et al.. (2001) Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci USA, 98 (16): 8966-71. [PMID:11459929]

8. Bowsher RR, Henry DP. (1983) Decarboxylation of p-tyrosine: a potential source of p-tyramine in mammalian tissues. J Neurochem, 40 (4): 992-1002. [PMID:6131938]

9. Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC et al.. (2009) The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci USA, 106 (47): 20081-6. [PMID:19892733]

10. Branchek TA, Blackburn TP. (2003) Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr Opin Pharmacol, 3 (1): 90-7. [PMID:12550748]

11. Brier ME, Bowsher RR, Mayer PR, Henry DP. (1991) Conversion of p-tyrosine to p-tyramine in the isolated perfused rat kidney: modulation by perfusate concentrations of p-tyrosine. Life Sci, 48: 901-907. [PMID:1997791]

12. Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL et al.. (2001) Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol, 60 (6): 1181-8. [PMID:11723224]

13. Chaytor JP, Crathorne B, Saxby MJ. (1975) The identification and significance of 2-phenylethylamine in foods. J Sci Food Agric, 26 (5): 593-8. [PMID:1160357]

14. Chiellini G, Frascarelli S, Ghelardoni S, Carnicelli V, Tobias SC, DeBarber A, Brogioni S, Ronca-Testoni S, Cerbai E, Grandy DK et al.. (2007) Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function. FASEB J, 21 (7): 1597-608. [PMID:17284482]

15. Cichero E, Espinoza S, Gainetdinov RR, Brasili L, Fossa P. (2013) Insights into the structure and pharmacology of the human trace amine-associated receptor 1 (hTAAR1): homology modelling and docking studies. Chem Biol Drug Des, 81 (4): 509-16. [PMID:22883051]

16. D'Andrea G, Terrazzino S, Fortin D, Farruggio A, Rinaldi L, Leon A. (2003) HPLC electrochemical detection of trace amines in human plasma and platelets and expression of mRNA transcripts of trace amine receptors in circulating leukocytes. Neurosci Lett, 346 (1-2): 89-92. [PMID:12850555]

17. Dale HH, Dixon WE. (1909) The action of pressor amines produced by putrefaction. J Physiol (Lond.), 39 (1): 25-44. [PMID:16992970]

18. Davenport AP. (2003) Peptide and trace amine orphan receptors: prospects for new therapeutic targets. Curr Opin Pharmacol, 3 (2): 127-34. [PMID:12681233]

19. David JC, Dairman W, Udenfriend S. (1974) Decarboxylation to tyramine: a major route of tyrosine metabolism in mammals. Proc Natl Acad Sci USA, 71 (5): 1771-5. [PMID:4525291]

20. Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L et al.. (2011) Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA). J Neurosci, 31 (47): 16928-40. [PMID:22114263]

21. Duan J, Martinez M, Sanders AR, Hou C, Saitou N, Kitano T, Mowry BJ, Crowe RR, Silverman JM, Levinson DF et al.. (2004) Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. Am J Hum Genet, 75 (4): 624-38. [PMID:15329799]

22. Durden DA, Philips SR. (1980) Kinetic measurements of the turnover rates of phenylethylamine and tryptamine in vivo in the rat brain. J Neurochem, 34: 1725-1732. [PMID:7381498]

23. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

24. Frascarelli S, Ghelardoni S, Chiellini G, Vargiu R, Ronca-Testoni S, Scanlan TS, Grandy DK, Zucchi R. (2008) Cardiac effects of trace amines: pharmacological characterization of trace amine-associated receptors. Eur J Pharmacol, 587 (1-3): 231-6. [PMID:18486124]

25. Galley G, Stalder H, Goergler A, Hoener MC, Norcross RD. (2012) Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012. Bioorg Med Chem Lett, 22 (16): 5244-8. [PMID:22795332]

26. Gloriam DE, Bjarnadóttir TK, Schiöth HB, Fredriksson R. (2005) High species variation within the repertoire of trace amine receptors. Ann N Y Acad Sci, 1040: 323-7. [PMID:15891052]

27. Grandy DK. (2007) Trace amine-associated receptor 1-Family archetype or iconoclast?. Pharmacol Ther, 116 (3): 355-90. [PMID:17888514]

28. Hannah P, Glover V, Sandler M. (1988) Tyramine in wine and beer. Lancet, 1 (8590): 879. [PMID:2895380]

29. Hart ME, Suchland KL, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS. (2006) Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues. J Med Chem, 49 (3): 1101-12. [PMID:16451074]

30. Hashiguchi Y, Nishida M. (2007) Evolution of trace amine associated receptor (TAAR) gene family in vertebrates: lineage-specific expansions and degradations of a second class of vertebrate chemosensory receptors expressed in the olfactory epithelium. Mol Biol Evol, 24 (9): 2099-107. [PMID:17634392]

31. Lewin AH. (2006) Receptors of mammalian trace amines. AAPS J, 8 (1): E138-45. [PMID:16584120]

32. Lewin AH, Miller GM, Gilmour B. (2011) Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class. Bioorg Med Chem, 19 (23): 7044-8. [PMID:22037049]

33. Lewin AH, Navarro HA, Mascarella SW. (2008) Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1. Bioorg Med Chem, 16 (15): 7415-23. [PMID:18602830]

34. Liberles SD, Buck LB. (2006) A second class of chemosensory receptors in the olfactory epithelium. Nature, 442: 645-650. [PMID:16878137]

35. Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC. (2005) Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics, 85 (3): 372-85. [PMID:15718104]

36. Lindemann L, Hoener MC. (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci, 26 (5): 274-81. [PMID:15860375]

37. Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL et al.. (2008) Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther, 324 (3): 948-56. [PMID:18083911]

38. Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP. (2009) International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature. Pharmacol Rev, 61 (1): 1-8. [PMID:19325074]

39. Miller GM. (2011) The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem, 116 (2): 164-76. [PMID:21073468]

40. Miyakawa M, Scanlan TS. (2006) Synthesis of [125I]-, [2H]-, and [3H]-labelled 3-iodothyronamine (T1AM). Synthetic Communications, 36: 891-902.

41. Nelson DA, Tolbert MD, Singh SJ, Bost KL. (2007) Expression of neuronal trace amine-associated receptor (Taar) mRNAs in leukocytes. J Neuroimmunol, 192 (1-2): 21-30. [PMID:17900709]

42. Pae CU, Drago A, Kim JJ, Patkar AA, Jun TY, Lee C, Mandelli L, De Ronchi D, Paik IH, Serretti A. (2008) TAAR6 variation effect on clinic presentation and outcome in a sample of schizophrenic in-patients: an open label study. Eur Psychiatry, 23 (6): 390-5. [PMID:18583103]

43. Pae CU, Yu HS, Amann D, Kim JJ, Lee CU, Lee SJ, Jun TY, Lee C, Paik IH, Patkar AA et al.. (2008) Association of the trace amine associated receptor 6 (TAAR6) gene with schizophrenia and bipolar disorder in a Korean case control sample. J Psychiatr Res, 42 (1): 35-40. [PMID:17097106]

44. Paterson IA, Juorio AV, Boulton AA. (1990) 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system?. J Neurochem, 55 (6): 1827-37. [PMID:2172461]

45. Piehl S, Hoefig CS, Scanlan TS, Köhrle J. (2011) Thyronamines--past, present, and future. Endocr Rev, 32 (1): 64-80. [PMID:20880963]

46. Reese EA, Bunzow JR, Arttamangkul S, Sonders MS, Grandy DK. (2007) Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine. J Pharmacol Exp Ther, 321 (1): 178-86. [PMID:17218486]

47. Reese EA, Norimatsu Y, Grandy MS, Suchland KL, Bunzow JR, Grandy DK. (2014) Exploring the determinants of trace amine-associated receptor 1's functional selectivity for the stereoisomers of amphetamine and methamphetamine. J Med Chem, 57 (2): 378-90. [PMID:24354319]

48. Regard JB, Kataoka H, Cano DA, Camerer E, Yin L, Zheng YW, Scanlan TS, Hebrok M, Coughlin SR. (2007) Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest, 117 (12): 4034-43. [PMID:17992256]

49. Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA et al.. (2011) TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci USA, 108 (20): 8485-90. [PMID:21525407]

50. Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velázquez-Sánchez C, Sotnikova TD, Morairty SR, Harmeier A, Groebke Zbinden K, Norcross RD et al.. (2012) Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol Psychiatry, 72 (11): 934-42. [PMID:22705041]

51. Roeder T. (2005) Tyramine and octopamine: ruling behavior and metabolism. Annu Rev Entomol, 50: 447-77. [PMID:15355245]

52. Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S et al.. (2004) 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med, 10 (6): 638-42. [PMID:15146179]

53. Schöneberg T, Hofreiter M, Schulz A, Römpler H. (2007) Learning from the past: evolution of GPCR functions. Trends Pharmacol Sci, 28 (3): 117-21. [PMID:17280721]

54. Sotnikova TD, Caron MG, Gainetdinov RR. (2009) Trace amine-associated receptors as emerging therapeutic targets. Mol Pharmacol, 76 (2): 229-35. [PMID:19389919]

55. Sotnikova TD, Zorina OI, Ghisi V, Caron MG, Gainetdinov RR. (2008) Trace amine associated receptor 1 and movement control. Parkinsonism Relat Disord, 14 Suppl 2: S99-102. [PMID:18585080]

56. Stalder H, Hoener MC, Norcross RD. (2011) Selective antagonists of mouse trace amine-associated receptor 1 (mTAAR1): discovery of EPPTB (RO5212773). Bioorg Med Chem Lett, 21 (4): 1227-31. [PMID:21237643]

57. Tan ES, Groban ES, Jacobson MP, Scanlan TS. (2008) Toward deciphering the code to aminergic G protein-coupled receptor drug design. Chem Biol, 15 (4): 343-53. [PMID:18420141]

58. Tan ES, Naylor JC, Groban ES, Bunzow JR, Jacobson MP, Grandy DK, Scanlan TS. (2009) The molecular basis of species-specific ligand activation of trace amine-associated receptor 1 (TAAR(1)). ACS Chem Biol, 4 (3): 209-20. [PMID:19256523]

59. Vanti WB, Muglia P, Nguyen T, Cheng R, Kennedy JL, George SR, O'Dowd BF. (2003) Discovery of a null mutation in a human trace amine receptor gene. Genomics, 82: 531-536. [PMID:14559210]

60. Wainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, Nelson DL. (2007) Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1. J Pharmacol Exp Ther, 320 (1): 475-85. [PMID:17038507]

61. Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP. (2007) The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav, 6 (7): 628-39. [PMID:17212650]

62. Xie Z, Miller GM. (2008) Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain. J Pharmacol Exp Ther, 325 (2): 617-28. [PMID:18182557]

63. Xie Z, Miller GM. (2009) Trace amine-associated receptor 1 as a monoaminergic modulator in brain. Biochem Pharmacol, 78 (9): 1095-104. [PMID:19482011]

64. Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM. (2007) Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro. J Pharmacol Exp Ther, 321 (1): 116-27. [PMID:17234900]

65. Xie Z, Westmoreland SV, Miller GM. (2008) Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes. J Pharmacol Exp Ther, 325 (2): 629-40. [PMID:18310473]

66. Zucchi R, Chiellini G, Scanlan TS, Grandy DK. (2006) Trace amine-associated receptors and their ligands. Br J Pharmacol, 149 (8): 967-78. [PMID:17088868]