TAAR1 explained

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene.[1] TAAR1 is an intracellular amine-activated and 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.

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 known endogenous ligands of the human TAAR1 (hTAAR1) receptor, by rank order of potency, are: tyramine > β-phenethylamine > dopamine = octopamine. Tryptamine and histamine also bind to hTAAR1 with lower affinity, whereas serotonin and norepinephrine did not have detectable affinity.

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.[2]

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. The human TAAR1 gene is thought to be an intronless gene.[3]

Tissue distribution

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 , and white blood cells.[4] In the duodenum, TAAR1 activation increases (GLP-1) and peptide YY (PYY) release; in the stomach, hTAAR1 activation has been observed to increase somatostatin (growth 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:

Ligands

Trace amine-associated receptor 1
Signal Transduction:Gs, Gq, GIRKs, β-arrestin 2
Primary Endogenous Agonists:tyramine,, octopamine, dopamine
Agonists:Endogenous: trace amines
Exogenous: RO5166017, amphetamine, methamphetamine, others
Antagonists:None characterized
Inverse Agonists:EPPTB
Pams:N/A
Nams:N/A
Iuphar Target Id:364
Drugbank Polypeptides Id:Q96RJ0
Hmdb Protein Id:HMDBP10805

Agonists

Trace amines

Trace amines are endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10  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 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 is:
tyramine > β-phenethylamine > dopamine = octopamine. Tryptamine and histamine also bind to the human TAAR1 with lower affinity, whereas serotonin and norepinephrine were inactive.

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

Partial agonists

Inverse agonists

Neutral antagonists

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. 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 in the associated monoamine neurons. As of 2010, of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.

In neurons with 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 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 (reuptake inhibition), but phosphorylation alone induces reverse transporter function (dopamine efflux).

Immune system

See also: Neuroimmune 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, and high concentrations are associated with schizophrenia. Low PEA levels and under-activation of TAAR1 also appears to be associated with ADHD.[10] [11] [12] It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression. 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. 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. Mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.

Medical reviews from February 2015 and 2016 noted that TAAR1-selective ligands have significant therapeutic potential for treating psychostimulant addictions (e.g., cocaine, amphetamine, methamphetamine, etc.).[13] 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.[14]

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.

In preclinical research on rats, TAAR1 activation in pancreatic cells promotes insulin, peptide YY, and GLP-1 secretion; therefore, TAAR1 is potentially a biological target for the treatment of obesity and diabetes.[15]

Lack of TAAR1 does not significantly affect sexual motivation and routine lipid and metabolic blood biochemical parameters, suggesting that future TAAR1-based therapies should have a favorable safety profile.[16]

Notes and References

  1. Web site: Entrez Gene: TAAR1 trace amine associated receptor 1.
  2. Gainetdinov RR, Hoener MC, Berry MD . Trace Amines and Their Receptors . Pharmacological Reviews . 70 . 3 . 549–620 . July 2018 . 29941461 . 10.1124/pr.117.015305 . free .
  3. Web site: TAAR1 . The Human Protein Atlas . 24 August 2017 .
  4. Berry MD, Gainetdinov RR, Hoener MC, Shahid M . Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges . Pharmacology & Therapeutics . 180 . 161–180 . December 2017 . 28723415 . 10.1016/j.pharmthera.2017.07.002 . free.
  5. Galley G, Beurier A, Décoret G, Goergler A, Hutter R, Mohr S, Pähler A, Schmid P, Türck D, Unger R, Zbinden KG, Hoener MC, Norcross RD . Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists . ACS Med Chem Lett . 7 . 2 . 192–197 . 2016 . 26985297 . 10.1021/acsmedchemlett.5b00449 . 4753552 .
  6. Cichero E, Francesconi V, Casini B, Casale M, Kanov E, Gerasimov AS, Sukhanov I, Savchenko A, Espinoza S, Gainetdinov RR, Tonelli M . Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays . Pharmaceuticals . 16 . 11 . November 2023 . 1632 . 38004497 . 10674299 . 10.3390/ph16111632 . free .
  7. Gursahani H, Jolas T, Martin M, Cotier S, Hughes S, Macfadden W, Parks G, Chepke C . Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion . CNS Spectrums . 28 . 2 . 2023 . 1092-8529 . 10.1017/S1092852923001396 . 222 . In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity..
  8. Scarano N, Espinoza S, Brullo C, Cichero E . Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands . Int J Mol Sci . 25 . 15 . July 2024 . 8226 . 39125796 . 11312273 . 10.3390/ijms25158226 . free . On the other hand, HTS approaches [100] followed by structure-activity optimization allowed for the discovery of the hTAAR1 antagonist RTI-7470-44, endowed with a species-specificity preference over mTAAR1 (Figure 11A) [99]. RTI-7470-44 displayed good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. In addition, RTI-7470-44 increased the spontaneous firing rate of mouse ventral tegmental area (VTA) dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. [...] Figure 11. (A) Chemical structures of the available hTAAR1 agonists: EPPTB [98], RTI-7470-44 [99], and 4c [33], [...] RTI-7470-44: hTAAR1 IC50 = 0.0084 μM, mTAAR1 IC50 = 1.190 μM..
  9. Decker AM, Brackeen MF, Mohammadkhani A, Kormos CM, Hesk D, Borgland SL, Blough BE . Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist . ACS Chem Neurosci . 13 . 7 . 1082–1095 . April 2022 . 35325532 . 9730857 . 10.1021/acschemneuro.2c00086 .
  10. Lindemann L, Hoener MC . A renaissance in trace amines inspired by a novel GPCR family . Trends Pharmacol. Sci. . 26 . 5 . 274–281 . May 2005 . 15860375 . 10.1016/j.tips.2005.03.007 . The dysregulation of TA levels has been linked to several diseases, which highlights the corresponding members of the TAAR family as potential targets for drug development. In this article, we focus on the relevance of TAs and their receptors to nervous system-related disorders, namely schizophrenia and depression; however, TAs have also been linked to other diseases such as migraine, attention deficit hyperactivity disorder, substance abuse and eating disorders [7,8,36]. Clinical studies report increased β-PEA plasma levels in patients suffering from acute schizophrenia [37] and elevated urinary excretion of β-PEA in paranoid schizophrenics [38], which supports a role of TAs in schizophrenia. As a result of these studies, β-PEA has been referred to as the body’s ‘endogenous amphetamine’ [39].
  11. Sotnikova TD, Caron MG, Gainetdinov RR . Trace amine-associated receptors as emerging therapeutic targets . Mol. Pharmacol. . 76 . 2 . 229–235 . August 2009 . 19389919 . 2713119 . 10.1124/mol.109.055970 . Although the functional role of trace amines in mammals remains largely enigmatic, it has been noted that trace amine levels can be altered in various human disorders, including schizophrenia, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, and phenylketonuria (Boulton, 1980; Sandler et al., 1980). It was generally held that trace amines affect the monoamine system indirectly via interaction with plasma membrane transporters [such as plasma membrane dopamine transporter (DAT)] and vesicular storage (Premont et al., 2001; Branchek and Blackburn, 2003; Berry, 2004; Sotnikova et al., 2004). ...
    Furthermore, DAT-deficient mice provide a model to investigate the inhibitory actions of amphetamines on hyperactivity, the feature of amphetamines believed to be important for their therapeutic action in ADHD (Gainetdinov et al., 1999; Gainetdinov and Caron, 2003). It should be noted also that the best-established agonist of TAAR1, β-PEA, shared the ability of amphetamine to induce inhibition of dopamine-dependent hyperactivity of DAT-KO mice (Gainetdinov et al., 1999; Sotnikova et al., 2004).
    Furthermore, if TAAR1 could be proven as a mediator of some of amphetamine's actions in vivo, the development of novel TAAR1-selective agonists and antagonists could provide a new approach for the treatment of amphetamine-related conditions such as addiction and/or disorders in which amphetamine is used therapeutically. In particular, because amphetamine has remained the most effective pharmacological treatment in ADHD for many years, a potential role of TAAR1 in the mechanism of the “paradoxical” effectiveness of amphetamine in this disorder should be explored..
  12. Berry MD . The potential of trace amines and their receptors for treating neurological and psychiatric diseases . Rev Recent Clin Trials . 2 . 1 . 3–19 . January 2007 . 18473983 . 10.2174/157488707779318107. changes in trace amines, in particular PE, have been identified as a possible factor for the onset of attention deficit/hyperactivity disorder (ADHD) [5, 27, 43, 78]. PE has been shown to induce hyperactivity and aggression, two of the cardinal clinical features of ADHD, in experimental animals [100]. Hyperactivity is also a symptom of phenylketonuria, which as discussed above is associated with a markedly elevated PE turnover [44]. Further, amphetamines, which have clinical utility in ADHD, are good ligands at trace amine receptors [2]. Of possible relevance in this aspect is modafanil, which has shown beneficial effects in ADHD patients [101] and has been reported to enhance the activity of PE at TAAR1 [102]. Conversely, methylphenidate, which is also clinically useful in ADHD, showed poor efficacy at the TAAR1 receptor [2]. In this respect it is worth noting that the enhancement of functioning at TAAR1 seen with modafanil was not a result of a direct interaction with TAAR1 [102].
    More direct evidence has been obtained recently for a role of trace amines in ADHD. Urinary PE levels have been reported to be decreased in ADHD patients in comparison to both controls and patients with autism [103-105]. Evidence for a decrease in PE levels in the brain of ADHD patients has also recently been reported [4]. In addition, decreases in the urine and plasma levels of the PE metabolite phenylacetic acid and the precursors phenylalanine and tyrosine have been reported along with decreases in plasma tyramine [103]. Following treatment with methylphenidate, patients who responded positively showed a normalization of urinary PE, whilst non-responders showed no change from baseline values [105].. 10.1.1.329.563 .
  13. Jing L, Li JX . Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction . Eur. J. Pharmacol. . 761 . 345–352 . August 2015 . 26092759 . 10.1016/j.ejphar.2015.06.019 . TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007) ... Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction. ... Given that TAAR1 is primarily located in the intracellular compartments and existing TAAR1 agonists are proposed to get access to the receptors by translocation to the cell interior (Miller, 2011), future drug design and development efforts may need to take strategies of drug delivery into consideration (Rajendran et al., 2010). . 4532615.
  14. Zhukov IS, Kubarskaya LG, Tissen IY, Kozlova AA, Dagayev SG, Kashuro VA, Vlasova OL, Sinitca EL, Karpova IV, Gainetdinov RR . Minimal Age-Related Alterations in Behavioral and Hematological Parameters in Trace Amine-Associated Receptor 1 (TAAR1) Knockout Mice . Cellular and Molecular Neurobiology . 40 . 2 . 273–282 . March 2020 . 31399838 . 10.1007/s10571-019-00721-4 . 199511689 .
  15. Raab S, Wang H, Uhles S, Cole N, Alvarez-Sanchez R, Künnecke B, Ullmer C, Matile H, Bedoucha M, Norcross RD, Ottaway-Parker N, Perez-Tilve D, Conde Knape K, Tschöp MH, Hoener MC, Sewing S . Incretin-like effects of small molecule trace amine-associated receptor 1 agonists . Mol Metab . 5 . 1 . 47–56 . 2016 . 26844206 . 4703809 . 10.1016/j.molmet.2015.09.015 .
  16. Zhukov IS, Ptukha MA, Zolotoverkhaja EA, Sinitca EL, Tissen IY, Karpova IV, Volnova AB, Gainetdinov RR . Evaluation of Approach to a Conspecific and Blood Biochemical Parameters in TAAR1 Knockout Mice . Brain Sciences . 12 . 5 . May 2022 . 614 . 35625001 . 9139149 . 10.3390/brainsci12050614 . free .