taar1 taar1 trace amine-associated receptor 1 (taar1) is a trace amine-associated receptor (taar) protein that in humans is encoded by the taar1 gene. taar1 is an intracellular amine-activated gs-coupled and gq-coupled g protein-coupled receptor (gpcr) that is primarily expressed in several peripheral organs and cells (e.g., the stomach, small intestine, duodenum, and white blood cells), astrocytes, and in the intracellular milieu within the presynaptic plasma membrane (i.e., axon terminal) of monoamine neurons in the central nervous system (cns). taar1 was discovered in 2001 by two independent groups of investigators, borowski et al. and bunzow et al. taar1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. taar1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the cns; it also affects immune system and neuroimmune system function through different mechanisms. taar1identifiersaliasestaar1, ta1, tar1, trar1, trace amine associated receptor 1, trace amine receptorexternal idsomim: 609333 mgi: 2148258 homologene: 24938 genecards: taar1 gene location (human)chr.chromosome 6 (human)band6q23.2start132,643,312 bpend132,659,182 bpgene location (mouse)chr.chromosome 10 (mouse)band10|10 a4start23,796,254 bpend23,797,367 bprna expression patternbgeehumanmouse (ortholog)top expressed inislet of langerhansright uterine tubeduodenumendometriumbloodmuscle tissuesmooth muscle tissuestomachurinary bladderbody of stomachtop expressed inislet of langerhansmucosa of small intestinemore reference expression databiogpsmore reference expression datagene ontologymolecular function g protein-coupled amine receptor activity signal transducer activity g protein-coupled receptor activity trace-amine receptor activity cellular component plasma membrane membrane integral component of membrane biological process signal transduction g protein-coupled receptor signaling pathway sources:amigo / quickgoorthologsspecieshumanmouseentrez134864111174ensemblensg00000146399ensmusg00000056379uniprotq96rj0q923y8refseq (mrna)nm_138327nm_053205refseq (protein)np_612200np_444435location (ucsc)chr 6: 132.64 – 132.66 mbchr 10: 23.8 – 23.8 mbpubmed searchwikidataview/edit humanview/edit mouse taar1 is a high-affinity receptor for amphetamine, methamphetamine, dopamine, and trace amines which mediates some of their cellular effects in monoamine neurons within the central nervous system. the primary endogenous ligands of the human taar1 (htaar1) receptor, by rank order of potency, are:tyramine > β-phenethylamine > dopamine = octopamine. discovery 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. further characterization of the functional role of taar1 and other receptors from this family was performed by other researchers including raul gainetdinov and his colleagues. structure taar1 shares structural similarities with the class a rhodopsin gpcr subfamily. it has 7 transmembrane domains with short n and c terminal extensions. 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. taar1 shares a predictive peptide motif with all other taars. this motif overlaps with transmembrane domain vii, and its identity is nsxxnpxxxxxxwf. taar1 and its homologues have ligand pocket vectors that utilize sets of 35 amino acids known to be involved directly in receptor-ligand interaction. gene all human taar genes are located on a single chromosome spanning 109 kb of human chromosome 6q23.1, 192 kb of mouse chromosome 10a4, and 216 kb of rat chromosome 1p12. each taar is derived from a single exon, except for taar2, which is coded by two exons. the human taar1 gene is thought to be an intronless gene. tissue distribution this diagram illustrates how taar1 activation induces incretin-like effects through the release of gastrointestinal hormones and influences food intake, blood glucose levels, and insulin release. taar1 expression in the periphery is indicated with "x". to date, taar1 has been identified and cloned in five 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, intestines and lungs, and at low levels in the brain. rhesus monkey taar1 and human taar1 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. htaar1 has also been identified in human astrocytes. outside of the human central nervous system, htaar1 also occurs as an intracellular receptor and is primarily expressed in the stomach, intestines, duodenum, pancreatic β-cells, and white blood cells. in the duodenum, taar1 activation increases glucagon-like peptide-1 (glp-1) and peptide yy (pyy) release; in the stomach, htaar1 activation has been observed to increase somatostatin (growth hormone-inhibiting hormone) secretion from delta cells. htaar1 is the only human trace amine-associated receptor subtype that is not expressed within the human olfactory epithelium. location within neurons taar1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals. in model cell systems, htaar1 has extremely poor membrane expression. a method to induce htaar1 membrane expression has been used to study its pharmacology via a bioluminescence resonance energy transfer camp assay. because taar1 is an intracellular receptor in monoamine neurons, exogenous taar1 ligands must enter the presynaptic neuron through a membrane transport protein or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce reuptake inhibition and neurotransmitter efflux. 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. 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. 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. receptor oligomers taar1 forms gpcr oligomers with monoamine autoreceptors in neurons in vivo. these and other reported taar1 hetero-oligomers include: taar1–d2sh taar1–α2a taar1–taar2 ligands trace amine-associated receptor 1transduction mechanismsgs, gq, girks, β-arrestin 2primary endogenous agoniststyramine, β-phenylethylamine, octopamine, dopamineagonistsendogenous: trace aminesexogenous: ro5166017, amphetamine, methamphetamine, othersneutral antagonistsnone characterizedinverse agonistsepptbpositive allosteric modulatorsn/anegative allosteric modulatorsn/aexternal resourcesiuphar/bps364drugbankq96rj0hmdbhmdbp10805 trace amines for a more comprehensive list, see trace amine § list of trace amines. trace amines are endogenous amines which act as agonists at taar1 and are present in extracellular concentrations of 0.1–10 nm in the brain, constituting less than 1% of total biogenic amines in the mammalian nervous system. some of the human trace amines include tryptamine, phenethylamine (pea), n-methylphenethylamine, p-tyramine, m-tyramine, n-methyltyramine, p-octopamine, m-octopamine, and synephrine. these share structural similarities with the three common monoamines: serotonin, dopamine, and norepinephrine. each ligand has a different potency, measured as increased cyclic amp (camp) concentration after the binding event. the rank order of potency for the primary endogenous ligands at htaar1 is:tyramine > β-phenethylamine > dopamine = octopamine. thyronamines 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, although it lacks monoamine transporter affinity and therefore has little effect in monoamine neurons of the central nervous system. 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. synthetic amphetamine and its substituted derivatives methamphetamine and mdma are all potent htaar1 agonists. upon association with taar1, they elicit increases in camp production similar to those of pea and p-tyramine. these compounds are structurally similar to pea and p-tyramine. benzofurans: 5-apb, 5-apdb, 6-apb, 6-apdb, 4-apb, 7-apb, 5-eapb, and 5-mapdb, as well as the benzodifuran 2c-b-fly, are htaar1 agonists that have an mdma-like pharmacodynamic profile. the methylphenethylamines are agonists of htaar1; these include α-methylphenethylamine (amphetamine), β-methylphenethylamine, n-methylphenethylamine (a trace amine), 2-methylphenethylamine, 3-methylphenethylamine, and 4-methylphenethylamine. in rats, lysergic acid diethylamide (lsd) is an agonist of rtaar1, but in humans it lacks any affinity for htaar1. certain 2-aminooxazoline compounds (ro5166017, ro5256390, ro5203648, and ro5263397) are orally bioavailable, highly potent, and selective agonists of taar1 in laboratory animals. ro5166017 or (s)-4--4,5-dihydrooxazol-2-ylamine is a selective taar1 agonist without significant activity at other targets. ro5203648 and ro5263397 are highly selective taar1 partial agonists. 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. ulotaront, investigational antipsychotic. partial agonists ralmitaront, investigational antipsychotic. inverse agonists epptb or n-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide is a selective htaar1 inverse agonist. neutral antagonists as of early 2018, no neutral antagonists for htaar1 have been characterized. function phenethylamine and amphetamine in a taar1-localized dopamine neuron via aadc amphetamine enters the presynaptic neuron across the neuronal membrane or through dat. once inside, it binds to taar1 or enters synaptic vesicles through vmat2. when amphetamine enters synaptic vesicles through vmat2, it collapses the vesicular ph gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through vmat2. when amphetamine binds to taar1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase a (pka) and protein kinase c (pkc), which subsequently phosphorylates dat. pka-phosphorylation causes dat to withdraw into the presynaptic neuron (internalize) and cease transport. pkc-phosphorylated dat may either operate in reverse or, like pka-phosphorylated dat, internalize and cease transport. amphetamine is also known to increase intracellular calcium, an effect which is associated with dat phosphorylation through a camkiiα-dependent pathway, in turn producing dopamine efflux. 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. 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. 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. 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. notably, amphetamine and trace amines possess high binding affinities for taar1, but not for monoamine autoreceptors. the effect of taar1 agonists on monoamine transporters in the brain appears to be site-specific. 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. 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. in neurons with co-localized taar1, taar1 agonists increase the concentrations of the associated monoamines in the synaptic cleft, thereby increasing post-synaptic receptor binding. through direct activation of g protein-coupled inwardly-rectifying potassium channels (girks), taar1 can reduce the firing rate of dopamine neurons, in turn preventing a hyper-dopaminergic state. amphetamine and trace amines can enter the presynaptic neuron either through dat or by diffusing across the neuronal membrane directly. as a consequence of dat uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter. 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). immune system