Trace amine associated receptor 1
Identifiers
Symbols	TAAR1; RP11-295F4.9; TA1; TAR1; TRAR1
External IDs	OMIM: 609333 MGI: 2148258 HomoloGene: 24938 IUPHAR: TA1 ChEMBL: 5857 GeneCards: TAAR1 Gene
Gene Ontology Molecular function • trace-amine receptor activity • signal transducer activity • receptor activity • G-protein coupled receptor activity Cellular component • plasma membrane • integral to membrane Biological process • G-protein coupled receptor signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	134864	111174
Ensembl	ENSG00000146399	ENSMUSG00000056379
UniProt	Q96RJ0	Q923Y8
RefSeq (mRNA)	NM_138327.1	NM_053205.1
RefSeq (protein)	NP_612200.1	NP_444435.1
Location (UCSC)	Chr 6: 132.97 – 132.97 Mb	Chr 10: 23.64 – 23.64 Mb
PubMed search	[1]	[2]
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Trace amine-associated receptor 1 is a protein that in humans is encoded by the TAAR1 gene.^[1]

The trace amine-associated receptor 1 is an amine-activated, G protein-coupled receptor (GPCR) located at the neural presynaptic membrane and on some lymphocytes. TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al.^[2][3] 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.^[4] TAAR1 is believed to be a key regulator of common and trace brain monoamines, and may also play some role in immune system function.^[5]

Discovery [link]

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 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.^[2][3]

Structure [link]

TAAR1 shares structural similarities with the rhodopsin/B-adrenergic receptor superfamily.^[3] It has 7 transmembrane domains with short N and C terminals.^[6] TAAR1 shares 62-96% sequence identity with TAARs2-15, which suggests that the TAAR subfamily is recently evolved; however, the low degree of similarity between TAAR1 orthologues suggests that they are rapidly evolving.^[2] In 2005, a predictive peptide fingerprint motif that TAAR1 has in common with all other TAARs was discovered. 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.^[4]

Gene [link]

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. TAAR1 is derived from a single exon. In fact, all TAARs are derived from one exon, except for TAAR2, which is coded by two exons.^[4]

Tissue distribution [link]

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.^[2] 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.^[7]

TAAR1 is the only TAAR subtype not found in the olfactory epithelium.^[8]

Location within neurons [link]

TAAR1 is expressed near the presynaptic membrane. Rat TAAR1 (rTAAR1) is not located on the membrane itself but rather located near the surface of the membrane.^[3] hTAAR1 has the same characteristic, which has led investigators to hypothesize that TAAR1 may reside primarily intracellularly, in vesicles.^[3][6]

TAAR1 and dopamine transporters (DAT) are colocalized in substantia nigra dopamine neurons of mice and rhesus monkeys.^[7]

Ligands [link]

Agonists [link]

Endogenous [link]

Trace amines and common biogenic monoamines [link]

Trace amines are those found in 0.1-10nMolar concentrations, constituting less than 1% of total biogenic amines in the mammalian nervous system.^[9] The endogenous trace amines are para/meta-tyramine, tryptamine, B-phenylethylamine (B-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 in cyclic AMP (cAMP) production after the binding event. The currently accepted rank order of ligand affinity for brain hTAAR1 is as follows: p-tyramine>B-PEA>octopamine>m-tyramine>dopamine>tryptamine>histamine>serotonin>norepinephrine.^[2][3][9] The EC50 values for cAMP production caused by p-tyramine and B-PEA binding events are 214 and 324 nM, respectively.^[3] Dopamine and serotonin have a 5 to 25-fold lower potency than either p-tyramine or B-PEA.^[4] The discrepancies in ligand potency may act to balance the differences in monoamine concentrations, common amines being less potent than trace amines.

Thyronamines [link]

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.^[10]

Synthetic [link]

• Amphetamine and the amphetamine-related compounds methamphetamine, lysergic acid diethylamide (LSD), 3,4-Methylenedioxymethamphetamine (MDMA), and 2,5-dimethoxy-4-iodoamphetamine (DOI) are all potent rTAAR1 agonists. Upon association with TAAR1, they elicit increases in cAMP production similar to those of B-PEA and p-tyramine. Unsurprisingly, these amphetamines-like compounds are structurally similar to B-PEA and p-tyramine.^[3][11]

• RO5166017 or (S)-4-[(ethylphenylamino)methyl]-4,5-dihydrooxazol-2-ylamine is a selective TAAR1 agonist without significant activity at other targets.^[12]

Antagonists [link]

• EPPTB or N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide is a selective TAAR1 antagonist.^[13]

Mechanisms of action [link]

Monoaminergic systems [link]

Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenalin release from sympathetic nerve endings and compete for catecholamine or serotonin binding sites on cognate receptors, transporters, and storage sites.^[9] 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 Gα_s G-protein activation of adenylyl cyclase.^[2][3][4] 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.^[11] These amines would then activate intracellular TAAR1. TAAR1 has been shown to have the opposite effect of monoamine autoreceptors.^[7][14] Dopamine autoreceptors provide feedback regulation of neurotransmitter release by activating the dopamine transporter (DAT), which internalizes synaptic dopamine. Active TAAR1 opposes the autoreceptor by inactivating the DAT.^[7][14] This is the proposed schematic: synaptic dopamine binds to the dopamine autoreceptor, which activates the DAT. Dopamine enters the presynaptic cells and binds to TAAR1, which increases adenylyl cyclase activity. This eventually allows for the translation of trace amines in the cytoplasm and activation of cyclic nucleotide-gated ion channels, which further activate TAAR1 and dump dopamine into the synapse. Through a series of phosphorylation events related to PKA and PKC, active TAAR1 inactivates DAT, preventing uptake of dopamine from the synapse.^[6] The presence of two presynaptic receptors with opposite abilities to regulate monoamine transporter function allows for regulation of the monoaminergic system.

In a different paper, Xie and Miller characterized the effect of methamphetamine on this system. Methamphetamine activation of TAAR1 severely biased the mechanism in favor of TAAR1 function, essentially rendering autoreceptors useless. TAAR1 activated by methamphetamine indirectly removes DAT from the membrane via a PKC-modulated internalization event. Internalized DAT is not able to remove dopamine from the synapse, resulting in a large dopamine efflux with a sustained synaptic presence.^[6]

Immune system [link]

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.^[5] 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.^[5]

Clinical significance [link]

B-PEA concentration in the brain is associated with major depressive disorder and schizophrenia. It is hypothesized that insufficient B-PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression (see "Discussion" in ^[2][9]). Some anti-depressants function by inhibiting MAO, which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells (see "Discussion" in ^[2][4]). Decreased B-PEA metabolism has been linked to schizophrenia, a logical finding considering excess B-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.^[4]

TAAR1 activation has also been connected to activation of lymphocyte immuno-characteristics via a PKA and PKC phosphorylation.^[5] In the future, problems with lymphocyte function may be reconciled by TAAR1 manipulation.

References [link]

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.