TAAR1

Trace amine-associated receptor 1 (TAAR1) is a is_associated_with::protein that in humans is encoded by the TAAR1 is_associated_with::gene. TAAR1 is an is_associated_with::amine-activated Gs- and Gq-coupled is_associated_with::G protein-coupled receptor (GPCR) that is located in several peripheral organs and circulating is_associated_with::lymphocytes, as well as within the presynaptic is_associated_with::membrane of is_associated_with::monoamine neurons in the is_associated_with::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 15 discovered is_associated_with::trace amine-associated receptors, which are so named for their ability to bind low-concentration, endogenous monoamines called is_associated_with::trace amines. TAAR1 is a key regulator of brain monoamines, and may also play some role in is_associated_with::immune system function.

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 is_associated_with::oligonucleotides with sequences related to is_associated_with::G protein-coupled receptors (GPCRs) of is_associated_with::serotonin and is_associated_with::dopamine to discover novel DNA sequences in is_associated_with::rat genomic is_associated_with::DNA and cDNA, which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1.

Structure
TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily. It has 7 is_associated_with::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 is_associated_with::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 is_associated_with::ligand pocket vectors that utilize a sets of 35 is_associated_with::amino acids known to be involved directly in receptor-ligand interaction.

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

Tissue distribution
To date, TAAR1 has been identified and cloned in four different is_associated_with::mammal is_associated_with::genomes: human, mouse, rat, is_associated_with::monkey, and is_associated_with::chimpanzee. In rats, is_associated_with::mRNA for TAAR1 is found at low to moderate levels in peripheral tissues like the is_associated_with::stomach, is_associated_with::kidney, and is_associated_with::lungs, and at low levels in the is_associated_with::brain is_associated_with::amygdala. is_associated_with::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 is_associated_with::species. These regions include the dorsal and ventral is_associated_with::caudate nucleus, is_associated_with::putamen, is_associated_with::substantia nigra, is_associated_with::nucleus accumbens, is_associated_with::ventral tegmental area, is_associated_with::locus coeruleus, amygdala, and is_associated_with::raphe nucleus.

TAAR1 is the only TAAR subtype not found in the is_associated_with::olfactory epithelium.

Location within neurons
Human TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons; 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 is_associated_with::bioluminescence resonance energy transfer cAMP assay.

Because TAAR1 is an intracellular receptor in monoamine neurons, TAAR1 ligands must enter the presynaptic neuron through a is_associated_with::membrane transport protein or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce is_associated_with::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.

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 is_associated_with::nervous system. The endogenous trace amines are para/meta-is_associated_with::tyramine, is_associated_with::tryptamine, is_associated_with::phenylethylamine (PEA), and para/meta-is_associated_with::octopamine. These share structural similarities with the three common monoamines: serotonin, dopamine, and is_associated_with::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 → is_associated_with::histamine → serotonin → norepinephrine. The EC50 values for cAMP production caused by p-tyramine and PEA binding events are 214 and 324 nM, respectively. Dopamine and serotonin have a 5 to 25-fold lower potency than either p-tyramine or PEA. The discrepancies in ligand potency may act to balance the differences in monoamine concentrations, common amines being less potent than trace amines.

Thyronamines
is_associated_with::Thyronamines are molecular derivatives of the is_associated_with::thyroid is_associated_with::hormone and are very important for is_associated_with::endocrine system function. is_associated_with::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 is_associated_with::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 is_associated_with::cardiac output.

Synthetic

 * is_associated_with::Amphetamine and the amphetamine-related compounds is_associated_with::methamphetamine, is_associated_with::3,4-methylenedioxymethamphetamine (MDMA), and is_associated_with::2,5-dimethoxy-4-iodoamphetamine (DOI) are all potent rTAAR1 is_associated_with::agonists. Upon association with TAAR1, they elicit increases in cAMP production similar to those of PEA and p-tyramine. Not surprisingly, these amphetamine-like compounds are structurally similar to PEA and p-tyramine.


 * is_associated_with::Benzofurans: is_associated_with::5-APB, is_associated_with::5-APDB, is_associated_with::6-APB, is_associated_with::6-APDB, is_associated_with::4-APB, is_associated_with::7-APB, is_associated_with::5-EAPB, and is_associated_with::5-MAPDB, as well as the is_associated_with::benzodifuran is_associated_with::2C-B-FLY, are hTAAR1 agonists that have an is_associated_with::MDMA-like pharmacodynamic profile.


 * The is_associated_with::methylphenethylamines are agonists of hTAAR1; these include is_associated_with::α-methylphenethylamine, is_associated_with::β-methylphenethylamine, is_associated_with::N-methylphenethylamine (not synthetic), is_associated_with::2-methylphenethylamine, is_associated_with::3-methylphenethylamine, and is_associated_with::4-methylphenethylamine.


 * In rats, is_associated_with::lysergic acid diethylamide (LSD) is an agonist, but it lacks any affinity for human TAAR1.


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


 * is_associated_with::RO5203648 and is_associated_with::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.

Antagonists

 * is_associated_with::EPPTB or N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide is a selective TAAR1 antagonist.

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 is_associated_with::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 is_associated_with::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 is_associated_with::cytoplasm. These amines would then activate intracellular TAAR1. Monoamine is_associated_with::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, is_associated_with::amphetamine and is_associated_with::trace amines bind to TAAR1, but not 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 is_associated_with::dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the is_associated_with::norepinephrine transporter (NET) and the is_associated_with::serotonin transporter (SERT) has only been evidenced by is_associated_with::messenger RNA (mRNA) expression.

In neurons with co-localized TAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in the is_associated_with::synaptic cleft, thereby heightening the response of the post-synaptic neuron. Through direct activation of is_associated_with::G protein-coupled inwardly-rectifying potassium channels and an indirect increase in dopamine autoreceptor signaling, TAAR1 reduces the firing rate of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state. Amphetamine and trace amines can enter the is_associated_with::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 is_associated_with::protein kinase A (PKA) and is_associated_with::protein kinase C (PKC) signaling, causes DAT is_associated_with::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
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 is_associated_with::phosphorylation cascades. 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. A recent paper showed that, along with TAAR1, is_associated_with::TAAR2 is required for full activity of trace amines in PMN cells.

is_associated_with::Phytohaemagglutinin upregulates hTAAR1 is_associated_with::mRNA in circulating is_associated_with::leukocytes; in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists. TAAR1 agonists (specifically, trace amines) have also been shown to induce is_associated_with::interleukin 4 secretion in is_associated_with::T-cells and is_associated_with::immunoglobulin E secretion in is_associated_with::B cells.

Clinical significance
Low is_associated_with::phenethylamine (PEA) concentration in the brain is associated with is_associated_with::major depressive disorder, and high concentrations are associated with is_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 ). Some antidepressants function by inhibiting is_associated_with::monoamine oxidase (MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells (see "Discussion" in ). Decreased PEA is_associated_with::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, is_associated_with::mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.

A large candidate gene association study published in September 2011 found significant differences in TAAR1 allele frequencies between a cohort of fibromyalgia patients and a chronic pain-free control group, suggesting this gene may play an important role in the pathophysiology of the condition; possibly presenting a target for therapeutic action.

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

Research
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. Unlike amphetamine, there is no evidence that cocaine is an agonist at TAAR1.