TAAR1

The TAAR1 was discovered in 2001 by two independent groups, Borowski et al. and Bunzow et al.. 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 NSXXNPXX[Y,H]XXX[Y,F]XWF. 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. == Tissue distribution ==

-like effects through the release of gastrointestinal hormones and influences food intake, blood glucose levels, and insulin release. In addition, TAAR1 signaling via the protein kinase A (PKA) pathway was predominantly associated with cell-surface TAAR1. Receptor oligomers TAAR1 forms GPCR oligomers with monoamine autoreceptors in neurons in vivo. ==Ligands==

Agonists Endogenous The known endogenous agonists of the TAAR1 include trace amines like β-phenethylamine (PEA), monoamine neurotransmitters like dopamine, and thyronamines like 3-iodothyronamine (T1AM). Trace amines are endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10nM 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), , , , , , , and synephrine. These share structural similarities with the three common monoamine neurotransmitters: 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 the human TAAR1 is: tyramine> β-phenethylamine> dopamine= octopamine. Unlike the monoamine neurotransmitters and trace amines, T1A is not a monoamine transporter (MAT) substrate, although it does still weakly interact with the MATs. 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. Other endogenous TAAR1 agonists include cyclohexylamine, isoamylamine, and trimethylamine, among others. Exogenous • 2-Aminoindanes • 4-Fluoroamphetamine – a potent TAAR1 partial agonist in rodents, but much less potent in humans • Selegiline (L-deprenyl) – a weak mouse TAAR1 partial agonist • Solriamfetol – a wakefulness-promoting agent acting as a dual norepinephrine–dopamine reuptake inhibitor (NDRI) and human TAAR1 agonist • AP163 – a TAAR1 agonist • Apomorphine – a dopamine agonist and antiparkinsonian agent, potent rodent TAAR1 agonist but not in humans • Asenapine – an atypical antipsychotic • Fenoterol – an adrenergic agonist • Guanfacine – an adrenergic agonist and ADHD medication • Idazoxan – adrenergic antagonist, potent mouse TAAR1 agonist but much weaker in humans • LK00764 – a rodent and human TAAR1 agonist • LY03020 • MPTP – a monoaminergic neurotoxin • Oxymetazoline – an adrenergic agonist • RG-7351 – a TAAR1 partial agonist and abandoned experimental antidepressant • RG-7410 – a TAAR1 agonist and abandoned experimental antipsychotic • Ring-methoxylated phenethylamines and amphetamines • RO5166017 – a selective rat and human TAAR1 near-full agonist but partial agonist in mice • RO5263397 – a selective rodent and human TAAR1 partial agonist Although amphetamine, methamphetamine, and MDMA are potent TAAR1 agonists in rodents, they are less potent at human TAAR1. MDMA shows very low potency and efficacy as a human TAAR1 agonist and has been described as inactive. The magnitude of TAAR1-mediated effects of amphetamines in humans at low doses is uncertain. Given the micromolar EC50 values reported for human TAAR1, TAAR1 agonism may be more relevant at high recreational doses. para-methoxyamphetamine (PMA), 4-methylthioamphetamine (4-MTA), MDEA, MBDB, 5-APDB, and 5-MAPDB, are inactive as human TAAR1 agonists. The negligible TAAR1 agonism with most cathinones might serve to enhance their effects and misuse potential as MRAs compared to their amphetamine counterparts. Selegiline is only a weak agonist of the mouse TAAR1, with dramatically lower potency than amphetamine or methamphetamine, and does not seem to have been assessed at the human TAAR1. • EPPTB (RO5212773) – a selective mouse TAAR1 inverse agonist but far less potent rat and human TAAR1 neutral antagonist A few other less well-known TAAR1 antagonists have also been discovered and characterized. Similarly, MDA and MDMA are weak to very weak partial agonists or antagonists of the human TAAR1 ( = 11% and 26%, respectively), albeit with very low potency. It has been claimed that rasagiline may act as a TAAR1 antagonist, but TAAR1 interactions have yet to be assessed or confirmed for this agent. == Function ==

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. One of the downstream effects of active TAAR1 is to increase cAMP in the presynaptic cell via Gαs G-protein activation of adenylyl cyclase. Activation of any these intracellular signaling pathways can result in DAT internalization ( reuptake inhibition), but phosphorylation alone induces reverse transporter function (dopamine efflux). Electrophysiological studies have linked TAAR1 activation to reduced excitability of midbrain dopamine neurons, including increased spontaneous firing in TAAR1 gene knockout animals and TAAR1-dependent suppression of neuronal firing in wild-type tissue. In HEK 293T cells stably expressing human TAAR1 (hTAAR1) and human DAT (hDAT), RO5166017 and RO5256390 were shown to bind to hDAT and competively inhibited hDAT-mediated dopamine reuptake, whereas ulotaront did not show detectable binding. In the same cell system, RO5256390 and ulotaront reduced dopamine reuptake, while RO5166017 increased reuptake, and these reuptake changes were -dependent. RO5166017 increased hDAT expression at the plasma membrane and potentiated amphetamine-induced reverse transport in a -dependent manner, whereas RO5256390 and ulotaront did not alter amphetamine-induced efflux. The authors concluded that although these agonists are relatively consistent in their effects on reducing VTA dopamine neuron firing, they are less consistent in effects on uptake and membrane expression, and only amphetamine induced -mediated 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 phosphorylation cascades. In a 2012 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, TAAR2 is required for full activity of trace amines in PMN cells. Phytohaemagglutinin upregulates mRNA in circulating leukocytes; in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists. TAAR1 agonists (specifically, trace amines) have also been shown to induce interleukin 4 secretion in T-cells and immunoglobulin E (IgE) secretion in B cells. Astrocyte-localized TAAR1 regulates EAAT2 levels and function in these cells; this has been implicated in methamphetamine-induced pathologies of the neuroimmune system. == Clinical significance ==

Low phenethylamine (PEA) concentration in the brain is associated with major depressive disorder, It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression. Despite wide distribution outside of the CNS and PNS, TAAR1 does not affect hematological functions and the regulation of thyroid hormones across different stages of ageing. Such data represent that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile. Research 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; this possibly presents a target for therapeutic intervention. Lack of TAAR1 significantly increase mice aggressive behavior , but does not affect sexual motivation and routine lipid and metabolic blood biochemical parameters, suggesting that future TAAR1-based therapies should have a favorable safety profile. Moreover, agonist RO5263397 reduces social aggression in brain serotonin-deficient tryptophan hydroxylase 2 knockout rats. This establishes the biological plausibility of TAAR1 agonism as a treatment for aggressive behavior. == See also ==