Trace amine receptor: Introduction

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 Gs 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 Gq protein, Gα16, 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

  1. Stop codon present in 10% of humans.
  2. 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].

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