Trace amine associated receptor 1
Symbols  ; TA1; TAR1; TRAR1
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Trace amine-associated receptor 1 (TAAR1) is a protein that in humans is encoded by the TAAR1 gene.[1] TAAR1 is an amine-activated Gs- and Gq-coupled G protein-coupled receptor (GPCR) that is located within the neural presynaptic membrane and on some lymphocytes.[2] TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al.[3][4] TAAR1 is one of 15 discovered trace amine-associated receptors, which are so named for their ability to bind low-concentration, endogenous monoamines called trace amines.[5][6] TAAR1 is a key regulator of brain monoamines,[5] and may also play some role in immune system function.[7]


  • Discovery 1
  • Structure 2
  • Gene 3
  • Tissue distribution 4
    • Location within neurons 4.1
  • Ligands 5
    • Agonists 5.1
      • Trace amines and common biogenic monoamines 5.1.1
      • Thyronamines 5.1.2
      • Synthetic 5.1.3
    • Antagonists 5.2
  • Function 6
    • Monoaminergic systems 6.1
    • Immune system 6.2
  • Clinical significance 7
    • Research 7.1
  • Notes 8
  • References 9


TAAR1 was discovered independently by Borowski et al. and Bunzow et al. in 2001. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures of oligonucleotides with sequences related to G protein-coupled receptors (GPCRs) of serotonin and dopamine to discover novel DNA sequences in rat genomic DNA and cDNA, which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1.[3][4]


TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily.[4] It has 7 transmembrane domains with short N and C terminal extensions.[8] TAAR1 is 62-96% identical with TAARs2-15, which suggests that the TAAR subfamily has recently evolved; while at the same time, the low degree of similarity between TAAR1 orthologues suggests that they are rapidly evolving.[3] TAAR1 shares a predictive peptide motif with all other TAARs. This motif overlaps with transmembrane domain VII, and its identity is NSXXNPXX[Y,H]XXX[Y,F]XWF. TAAR1 and its homologues have ligand pocket vectors that utilize a sets of 35 amino acids known to be involved directly in receptor-ligand interaction.[6]


All TAAR genes are located on a single chromosome spanning 109kb of human chromosome 6q23.1, 192 kb of mouse chromosome 10A4, and 216 kb or rat chromosome 1p12. Each TAAR is derived from a single exon, except for TAAR2, which is coded by two exons.[6]

Tissue distribution

To date, TAAR1 has been identified and cloned in four different mammal genomes: human, mouse, rat, monkey, and chimpanzee. In rats, mRNA for TAAR1 is found at low to moderate levels in peripheral tissues like the stomach, kidney, and lungs, and at low levels in the brain amygdala.[3] Rhesus monkey Taar1 and human TAAR1 (hTAAR1) share high sequence similarity, and TAAR1 mRNA is highly expressed in the same important monoaminergic regions of both species. These regions include the dorsal and ventral caudate nucleus, putamen, substantia nigra, nucleus accumbens, ventral tegmental area, locus coeruleus, amygdala, and raphe nucleus.[9]

TAAR1 is the only TAAR subtype not found in the olfactory epithelium.[10]

Location within neurons

Human TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons;[5][11] in model cell systems, hTAAR1 has extremely poor membrane expression.[11] A method to induce hTAAR1 membrane expression has been used to study its pharmacology via a bioluminescence resonance energy transfer cAMP assay.[11]

Because TAAR1 is an intracellular receptor in monoamine neurons, TAAR1 ligands must enter the presynaptic neuron through a membrane transport protein[note 1] or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce reuptake inhibition and neurotransmitter efflux.[5] Consequently, the efficacy of a particular TAAR1 ligand in producing these effects in different monoamine neurons is a function of both its binding affinity at TAAR1 and its capacity to move across the presynaptic membrane at each type of neuron.[5] The variability between a TAAR1 ligand's substrate affinity at the various monoamine transporters accounts for much of the difference in its capacity to produce neurotransmitter release and reuptake inhibition in different types of monoamine neurons.[5] E.g., a TAAR1 ligand which can easily pass through the norepinephrine transporter, but not the serotonin transporter, will produce – all else equal – markedly greater TAAR1-induced effects in norepinephrine neurons as compared to serotonin neurons.



Trace amines and common biogenic monoamines

Trace amines are those found in 0.1-10 nM concentrations, constituting less than 1% of total biogenic amines in the mammalian nervous system.[12] The endogenous trace amines are para/meta-tyramine, tryptamine, phenylethylamine (PEA), and para/meta-octopamine. These share structural similarities with the three common monoamines: serotonin, dopamine, and norepinephrine. Each ligand has a different potency, measured as increases cyclic AMP (cAMP) concentration after the binding event. The currently accepted rank order of ligand affinity for brain hTAAR1 is as follows: p-tyramine → PEA → octopamine → m-tyramine → dopamine → tryptamine → histamine → serotonin → norepinephrine.[3][4][12] The EC50 values for cAMP production caused by p-tyramine and PEA binding events are 214 and 324 nM, respectively.[4] Dopamine and serotonin have a 5 to 25-fold lower potency than either p-tyramine or PEA.[6] The discrepancies in ligand potency may act to balance the differences in monoamine concentrations, common amines being less potent than trace amines.


Thyronamines are molecular derivatives of the thyroid hormone and are very important for endocrine system function. 3-Iodothyronamine (T1AM) is the most potent TAAR1 agonist yet discovered. Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output. This relationship is not typical of the endocrine system, indicating that TAAR1 activity may not be coupled to G-proteins in some tissues, or that T1AM may interact with other receptor subtypes.[13]


  • RO5166017 or (S)-4-[(ethylphenylamino)methyl]-4,5-dihydrooxazol-2-ylamine is a selective TAAR1 agonist without significant activity at other targets.[16]
  • RO5203648 is a first in class selective, high affinity TAAR1 partial agonist. RO5203648 demonstrated clear antidepressant and anti-psychotic activity, additionally it attenuated drug self-administration and exhibited wakefulness promoting and cognition enhancing properties in murine and simian models.[17]


  • EPPTB or N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide is a selective TAAR1 antagonist.[18]


A dopamine neuron with co-localized TAAR1

A pharmacodynamic model of amphetamine and TAAR1
via AADC
Amphetamine or a trace amine enters the presynaptic neuron directly across the neuronal membrane or through DAT. Once inside, it binds to TAAR1. When activated, TAAR1 reduces dopamine receptor firing rate and triggers PKA and PKC signaling, resulting in DAT phosphorylation. Phosphorylated DAT then either operates in reverse (causing effluxion and reuptake inhibition) or withdraws into the presynaptic neuron and ceases transport.

Monoaminergic systems

Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release from sympathetic nerve endings and compete for catecholamine or serotonin binding sites on cognate receptors, transporters, and storage sites.[12] Today, they are believed to play a much more dynamic role by regulating monoaminergic systems in the brain.

One of the downstream effects of active TAAR1 is to increase cAMP in the presynaptic cell via Gαs G-protein activation of adenylyl cyclase.[3][4][6] This alone can have a multitude of cellular consequences. A main function of the cAMP may be to up-regulate the expression of trace amines in the cell cytoplasm.[14] These amines would then activate intracellular TAAR1. Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[5] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[5] The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific.[5] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of TAAR1 co-localization in the associated monoamine neurons.[5] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[5]

In neurons with co-localized TAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in the synaptic cleft, thereby heightening the response of the post-synaptic neuron.[5] Through direct activation of G protein-coupled inwardly-rectifying potassium channels and increased dopamine release, TAAR1 reduces the firing rate of post-synaptic dopamine receptors, preventing a hyper-dopaminergic state.[19][20][21] Amphetamine and trace amines can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[5] As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter.[5] Upon entering the presynaptic neuron, these compounds activate TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[5][22]

Immune system

Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics. In the immune system, TAAR1 transmits signals through active PKA and PKC phosphorylation cascades.[7] In a recent study, Panas et al. observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system.[7] A recent paper showed that, along with TAAR1, TAAR2 is required for full activity of trace amines in PMN cells.[23]

Clinical significance

Low phenethylamine (PEA) concentration in the brain is associated with major depressive disorder, and high concentrations are associated with schizophrenia. It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression (see "Discussion" in [3][12]). Some antidepressants function by inhibiting monoamine oxidase (MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells (see "Discussion" in [3][6]). Decreased PEA metabolism has been linked to schizophrenia, a logical finding considering excess PEA would result in over-activation of TAAR1 and prevention of monoamine transporter function. Interestingly, mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.[6]

TAAR1 activation has also been connected to activation of lymphocyte immuno-characteristics via a PKA and PKC phosphorylation.[7] In the future, problems with lymphocyte function may be reconciled by TAAR1 manipulation.


Preclinical research indicates that TAAR1 is a promising target in treating cocaine addiction, as it seems to function as a "molecular brake" to the effects related to cocaine addiction.[24] Unlike amphetamine, there is no evidence that cocaine is an agonist at TAAR1.


  1. ^ In dopamine, norepinephrine, and serotonin neurons, the primary membrane transporters are DAT, NET, and SERT respectively.[5]


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    The effect of β-carbon substitution on the phenylethylamine side chain was also investigated (Table 3). A β-methyl substituent was well tolerated compared with β-PEA. In fact, S-(–)-β-methyl-β-PEA was as potent as β-PEA at human TAAR1. β-Hydroxyl substitution was, however, not tolerated compared with β-PEA. In both cases of β-substitution, enantiomeric selectivity was demonstrated.
    In contrast to a methyl substitution on the β-carbon, an α-methyl substitution reduced potency by ∼10-fold for d-amphetamine and 16-fold for l-amphetamine relative to β-PEA (Table 4). N-Methyl substitution was fairly well tolerated; however, N,N-dimethyl substitution was not.
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     • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.