Wikipedia

TAAR1

Trace amine-associated receptor 1(TAAR1) is atrace amine-associated receptor(TAAR)proteinthat in humans is encoded by theTAAR1gene.[5]TAAR1 is an intracellularamine-activatedGs-coupledandGq-coupledG protein-coupled receptor(GPCR) that is primarily expressed in several peripheral organs and cells (e.g., thestomach,small intestine,duodenum,andwhite blood cells),astrocytes,and in theintracellular milieuwithin the presynapticplasma membrane(i.e.,axon terminal) ofmonoamineneuronsin thecentral nervous system(CNS).[6][7][8][9]TAAR1 was discovered in 2001 by two independent groups of investigators, Borowskiet al.and Bunzowet al.[10][11]TAAR1 is one of six functionalhuman trace amine-associated receptors,which are so named for their ability to bindendogenousamines that occur in tissues at trace concentrations.[12][13]TAAR1 plays a significant role in regulatingneurotransmissionindopamine,norepinephrine,andserotoninneurons in the CNS;[7][12]it also affectsimmune systemandneuroimmune systemfunction through different mechanisms.[14][15][16][17]

TAAR1
Identifiers
AliasesTAAR1,TA1, TAR1, TRAR1, trace amine associated receptor 1, Trace amine receptor
External IDsOMIM:609333;MGI:2148258;HomoloGene:24938;GeneCards:TAAR1;OMA:TAAR1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

134864

111174

Ensembl

ENSG00000146399

ENSMUSG00000056379

UniProt

Q96RJ0

Q923Y8

RefSeq (mRNA)

NM_138327

NM_053205

RefSeq (protein)

NP_612200

NP_444435

Location (UCSC)Chr 6: 132.64 – 132.66 MbChr 10: 23.8 – 23.8 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

TAAR1 is a high-affinity receptor foramphetamine,methamphetamine,dopamine,andtrace amineswhich mediates some of their cellular effects in monoamine neurons within thecentral nervous system.[7][12]

The primary known endogenous ligands of the human TAAR1 (hTAAR1) receptor, by rank order of potency, are:tyramine>β-phenethylamine>dopamine=octopamine.[6]Tryptamineandhistaminealso bind to hTAAR1 with loweraffinity,whereasserotoninandnorepinephrinedid not have detectable affinity.[10]

Discovery

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TAAR1 was discovered independently by Borowskiet al.and Bunzowet al.in 2001. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures ofoligonucleotideswith sequences related toG protein-coupled receptors(GPCRs) ofserotoninanddopamineto discover novelDNA sequencesinratgenomicDNAandcDNA,which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1.[10][11]Further characterization of the functional role of TAAR1 and other receptors from this family was performed by other researchers includingRaul Gainetdinovand his colleagues.[18]

Structure

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TAAR1 shares structural similarities with theclass A rhodopsinGPCRsubfamily.[11]It has 7transmembrane domainswith shortNandC terminalextensions.[19]TAAR1 is 62–96% identical with TAARs2-15, which suggests that the TAARsubfamilyhas recentlyevolved;while at the same time, the low degree of similarity between TAAR1orthologuessuggests that they are rapidly evolving.[10]TAAR1 shares a predictivepeptidemotifwith 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 haveligandpocket vectors that utilize sets of 35amino acidsknown to be involved directly in receptor-ligand interaction.[13]

Gene

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All human TAAR genes are located on a singlechromosomespanning 109 kb ofhumanchromosome 6q23.1, 192 kb ofmousechromosome 10A4, and 216 kb of rat chromosome 1p12. Each TAAR is derived from a singleexon,except forTAAR2,which is coded by two exons.[13]The humanTAAR1gene is thought to be anintronlessgene.[20]

Tissue distribution

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This diagram illustrates how TAAR1 activation inducesincretin-like effects through the release of gastrointestinal hormones and influences food intake,blood glucoselevels, andinsulinrelease.[9]TAAR1 expression in the periphery is indicated with "x".[9]

To date, TAAR1 has been identified and cloned in five differentmammalgenomes:human, mouse, rat,monkey,andchimpanzee.In rats,mRNAfor TAAR1 is found at low to moderate levels in peripheral tissues like thestomach,kidney,intestines[21]andlungs,and at low levels in thebrain.[10]Rhesus monkeyTaar1 and human TAAR1 share high sequence similarity, and TAAR1 mRNA is highly expressed in the same important monoaminergic regions of bothspecies.These regions include the dorsal and ventralcaudate nucleus,putamen,substantia nigra,nucleus accumbens,ventral tegmental area,locus coeruleus,amygdala, andraphe nucleus.[6][22]hTAAR1 has also been identified in human astrocytes.[6][14]

Outside of the human central nervous system, hTAAR1 also occurs as an intracellular receptor and is primarily expressed in thestomach,intestines,[21]duodenum,[21]pancreaticβ-cells,andwhite blood cells.[9][21]In the duodenum, TAAR1 activation increasesglucagon-likepeptide-1(GLP-1) andpeptide YY(PYY) release;[9]in the stomach, hTAAR1 activation has been observed to increasesomatostatin(growthhormone-inhibitinghormone) secretion fromdelta cells.[9]

hTAAR1 is the onlyhuman trace amine-associated receptorsubtype that is not expressed within the humanolfactory epithelium.[23]

Location within neurons

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TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals.[7][12][24]In model cell systems, hTAAR1 has extremely poor membrane expression.[24]A method to induce hTAAR1 membrane expression has been used to study its pharmacology via abioluminescence resonance energy transfercAMP assay.[24]

Because TAAR1 is an intracellular receptor in monoamine neurons,exogenousTAAR1 ligands must enter the presynaptic neuron through amembrane transport protein[note 1]or be able to diffuse across the presynaptic membrane in order to reach the receptor and producereuptake inhibitionandneurotransmitter efflux.[12]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.[12]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.[12]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

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TAAR1 formsGPCR oligomerswith monoamine autoreceptors in neuronsin vivo.[25][26]These and other reported TAAR1 hetero-oligomers include:

[note 2] in the TAAR1- D2sh example shows that TAAR1 can be located at cell membranes, and in the case of enterochromaffin cells in the gut epithelium, TAAR1 can be activated by high doses of dietary 'trace' amines, proximal to vesicles packed with catecholamines, impacting the vagal nerve system and CNS. This raises questions about where T1AM might find TAAR1 and cause similar unexpected nerve firing.

Ligands

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Trace amine-associated receptor 1
Transduction mechanismsGs,Gq,GIRKs,β-arrestin 2
Primaryendogenous agoniststyramine,β-phenylethylamine,octopamine,dopamine
AgonistsEndogenous:trace amines
Exogenous:RO5166017,amphetamine,methamphetamine,others
Neutral antagonistsNone characterized
Inverse agonistsEPPTB
Positive allosteric modulatorsN/A
Negative allosteric modulatorsN/A
External resources
IUPHAR/BPS364
DrugBankQ96RJ0
HMDBHMDBP10805

Agonists

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Trace amines

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For a more comprehensive list, seeTrace amine § List of trace amines.

Trace aminesare endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10nMTooltip nanomolarin the brain, constituting less than 1% of total biogenic amines in the mammaliannervous system.[28]Some of the human trace amines includetryptamine,phenethylamine(PEA),N-methylphenethylamine,p-tyramine,m-tyramine,N-methyltyramine,p-octopamine,m-octopamine,andsynephrine.These share structural similarities with the three common monoamines:serotonin,dopamine,andnorepinephrine.Each ligand has a different potency, measured as increasedcyclic AMP(cAMP) concentration after the binding event.

The rank order of potency for the primary endogenous ligands athTAAR1is:
tyramine>β-phenethylamine>dopamine=octopamine.[6][10]Tryptamineandhistaminealso bind to the human TAAR1 with loweraffinity,whereasserotoninandnorepinephrinewere inactive.[10]

Thyronamines

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Thyronaminesare molecular derivatives of thethyroidhormoneand are very important forendocrine systemfunction.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 thecentral nervous system.Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreasedbody temperatureandcardiac output.

Synthetic

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Partial agonists

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  • Ralmitaront(RG-7906, RO-6889450), investigational antipsychotic.

Inverse agonists

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Neutral antagonists

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Function

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Phenethylamine and amphetamine in a TAAR1-localized dopamine neuron
viaAADC
Amphetamine enters the presynaptic neuron across the neuronal membrane or throughDAT.[12]Once inside, it binds toTAAR1or enters synaptic vesicles throughVMAT2.[12][44]When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into thecytosol(light tan-colored area) through VMAT2.[44][45]When amphetamine binds to TAAR1, it reduces thefiring rateof the dopamine neuron viaG protein-coupled inwardly rectifying potassium channels(GIRKs) and activatesprotein kinase A(PKA) andprotein kinase C(PKC), which subsequently phosphorylate DAT.[12][46][47]PKA phosphorylationcauses DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[12]PKC-phosphorylatedDAT may either operate in reverse or, likePKA-phosphorylatedDAT, internalize and cease transport.[12]Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through aCAMKIIα-dependent pathway, in turn producing dopamine efflux.[48][49]

Monoaminergic systems

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Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release fromsympathetic nerve endingsand compete forcatecholamineor serotonin binding sites on cognate receptors, transporters, and storage sites.[28]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 increasecAMPin the presynapticcellvia GαsG-protein activation ofadenylyl cyclase.[10][11][13]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 cellcytoplasm.[29]These amines would then activate intracellular TAAR1. Monoamineautoreceptors(e.g.,D2short,presynaptic α2,andpresynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[12]Notably,amphetamineand trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[12][7]The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific.[12]Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of TAAR1co-localizationin the associated monoamine neurons.[12]As of 2010,co-localizationof TAAR1 and thedopamine transporter(DAT) has been visualized in rhesus monkeys, butco-localizationof TAAR1 with thenorepinephrine transporter(NET) and theserotonin transporter(SERT) has only been evidenced bymessenger RNA(mRNA) expression.[12]

In neurons withco-localizedTAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in thesynaptic cleft,thereby increasing post-synaptic receptor binding.[12]Through direct activation ofG protein-coupled inwardly-rectifying potassium channels(GIRKs), TAAR1 can reduce thefiring rateof dopamine neurons, in turn preventing a hyper-dopaminergic state.[33][46][47]Amphetamine and trace amines can enter thepresynaptic neuroneither throughDATor by diffusing across the neuronal membrane directly.[12]As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter.[12]Upon entering the presynaptic neuron, these compounds activate TAAR1 which, throughprotein kinase A(PKA) andprotein kinase C(PKC) signaling, causes DATphosphorylation.Phosphorylation by either protein kinase can result in DATinternalization(non-competitivereuptake inhibition), butPKC-mediatedphosphorylation alone induces reverse transporter function (dopamineefflux).[12][50]

Immune system

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See also:Neuroimmune system

Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics.[16]In the immune system, TAAR1 transmits signals through active PKA and PKCphosphorylationcascades.[16]In a 2012 study, Panaset 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.[16]A recent paper showed that, along with TAAR1,TAAR2is required for full activity of trace amines inPMN cells.[17]

PhytohaemagglutininupregulateshTAAR1mRNAin circulatingleukocytes;[6]in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists.[6]TAAR1 agonists (specifically, trace amines) have also been shown to induceinterleukin 4secretion inT-cellsandimmunoglobulin E(IgE) secretion inB cells.[6]

Astrocyte-localized TAAR1 regulatesEAAT2levels and function in these cells;[14]this has been implicated in methamphetamine-induced pathologies of theneuroimmune system.[14]

Clinical significance

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Lowphenethylamine(PEA) concentration in the brain is associated withmajor depressive disorder,[10][28][51]and high concentrations are associated withschizophrenia.[51][52]Low PEA levels and under-activation of TAAR1 also appears to be associated withADHD.[51][52][53]It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression.[10][28]Some antidepressants function by inhibitingmonoamine oxidase(MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells.[10][13]Decreased PEAmetabolismhas been linked to schizophrenia, a logical finding considering excess PEA would result in over-activation of TAAR1 and prevention of monoamine transporter function.Mutationsin region q23.1 ofhuman chromosome 6– the same chromosome that codes for TAAR1 – have been linked to schizophrenia.[13]

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.).[7][8]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.[54]

Research

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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.[55]

In preclinical research on rats, TAAR1 activation in pancreatic cells promotesinsulin,peptide YY,andGLP-1secretion;[56][non-primary source needed]therefore, TAAR1 is potentially a biological target for the treatment ofobesityanddiabetes.[56][non-primary source needed]

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.[57]

Notes

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  1. ^Indopamine,norepinephrine,andserotoninneurons, the primary membrane transporters areDAT,NET,andSERTrespectively.[12]
  2. ^TAAR1–D2sh is a presynapticheterodimerwhich involves the relocation of TAAR1 from the intracellular space to D2sh at theplasma membrane,increased D2sh agonistbinding affinity,andsignal transductionthrough the calcium–PKC–NFATpathway andG-proteinindependentPKB–GSK3pathway.[7][27]

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000146399–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000056379–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^"Entrez Gene: TAAR1 trace amine associated receptor 1".
  6. ^abcdefghiMaguire JJ, Davenport AP (20 February 2018)."Trace amine receptor: TA1receptor ".IUPHAR/BPS Guide to PHARMACOLOGY.International Union of Basic and Clinical Pharmacology.Retrieved16 July2018.
    Tissue Distribution
    CNS (region specific) & several peripheral tissues:
    Stomach > amygdala, kidney, lung, small intestine > cerebellum, dorsal root ganglion, hippocampus, hypothalamus, liver, medulla oblongata, pancreas, pituitary gland, pontine reticular formation, prostate, skeletal muscle, spleen....
    Leukocytes...Pancreatic islet β cells... Primary Tonsillar B Cells... Circulating leukocytes of healthy subjects (upregulation occurs upon addition of phytohaemagglutinin).
    Species: Human...
    In the brain (mouse, rhesus monkey) the TA1 receptor localises to neurones within the momaminergic pathways and there is emerging evidence for a modulatory role for TA1 on function of these systems. Co-expression of TA1 with the dopamine transporter (either within the same neurone or in adjacent neurones) implies direct/indirect modulation of CNS dopaminergic function. In cells expressing both human TA1 and a monoamine transporter (DAT, SERT or NET) signalling via TA1 is enhanced [26,48,50–51]....
    Functional Assays...
    Mobilization of internal calcium in RD-HGA16 cells transfected with unmodified human TA1
    Response measured: Increase in cytopasmic calcium...
    Measurement of cAMP levels in human cultured astrocytes.
    Response measured: cAMP accumulation...
    Activation of leukocytes
    Species: Human
    Tissue: PMN, T and B cells
    Response measured: Chemotactic migration towards TA1 ligands (β-Phenylethylamine, tyramine and 3-iodothyronamine), trace amine induced IL-4 secretion (T-cells) and trace amine induced regulation of T cell marker RNA expression, trace amine induced IgE secretion in B cells.
  7. ^abcdefghGrandy DK, Miller GM, Li JX (February 2016).""TAARgeting Addiction" -The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference ".Drug Alcohol Depend.159:9–16.doi:10.1016/j.drugalcdep.2015.11.014.PMC4724540.PMID26644139.TAAR1 is a high-affinity receptor for METH/AMPH and DA... This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA)
  8. ^abJing L, Li JX (August 2015)."Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction".Eur. J. Pharmacol.761:345–352.doi:10.1016/j.ejphar.2015.06.019.PMC4532615.PMID26092759.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).
  9. ^abcdefghiBerry MD, Gainetdinov RR, Hoener MC, Shahid M (December 2017)."Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges".Pharmacology & Therapeutics.180:161–180.doi:10.1016/j.pharmthera.2017.07.002.PMID28723415.
  10. ^abcdefghijkBorowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. (July 2001)."Trace amines: identification of a family of mammalian G protein-coupled receptors".Proceedings of the National Academy of Sciences of the United States of America.98(16): 8966–8971.Bibcode:2001PNAS...98.8966B.doi:10.1073/pnas.151105198.PMC55357.PMID11459929.
  11. ^abcdefBunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. (December 2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor".Molecular Pharmacology.60(6): 1181–1188.doi:10.1124/mol.60.6.1181.PMID11723224.
  12. ^abcdefghijklmnopqrstuvMiller GM (January 2011)."The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity".Journal of Neurochemistry.116(2): 164–176.doi:10.1111/j.1471-4159.2010.07109.x.PMC3005101.PMID21073468.
  13. ^abcdefLindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC (March 2005). "Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors".Genomics.85(3): 372–385.doi:10.1016/j.ygeno.2004.11.010.PMID15718104.
  14. ^abcdCisneros IE, Ghorpade A (October 2014)."Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes".Neuropharmacology.85:499–507.doi:10.1016/j.neuropharm.2014.06.011.PMC4315503.PMID24950453.TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function.
  15. ^Rogers TJ (2012)."The molecular basis for neuroimmune receptor signaling".J Neuroimmune Pharmacol.7(4): 722–724.doi:10.1007/s11481-012-9398-4.PMC4011130.PMID22935971.
  16. ^abcdPanas MW, Xie Z, Panas HN, Hoener MC, Vallender EJ, Miller GM (December 2012)."Trace amine associated receptor 1 signaling in activated lymphocytes".Journal of Neuroimmune Pharmacology.7(4): 866–876.doi:10.1007/s11481-011-9321-4.PMC3593117.PMID22038157.
  17. ^abBabusyte A, Kotthoff M, Fiedler J, Krautwurst D (March 2013). "Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2".Journal of Leukocyte Biology.93(3): 387–394.doi:10.1189/jlb.0912433.PMID23315425.S2CID206996784.
  18. ^Gainetdinov RR, Hoener MC, Berry MD (July 2018)."Trace Amines and Their Receptors".Pharmacological Reviews.70(3): 549–620.doi:10.1124/pr.117.015305.PMID29941461.
  19. ^Xie Z, Miller GM (November 2009)."Trace amine-associated receptor 1 as a monoaminergic modulator in brain".Biochemical Pharmacology.78(9): 1095–1104.doi:10.1016/j.bcp.2009.05.031.PMC2748138.PMID19482011.
  20. ^"TAAR1".The Human Protein Atlas.Retrieved24 August2017.
  21. ^abcdBugda Gwilt K, González DP, Olliffe N, Oller H, Hoffing R, Puzan M, et al. (December 2019)."Actions of Trace Amines in the Brain-Gut-Microbiome Axis via Trace Amine-Associated Receptor-1 (TAAR1)"(PDF).Cellular and Molecular Neurobiology.40(2): 191–201.doi:10.1007/s10571-019-00772-7.PMID31836967.S2CID209339614.
  22. ^Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, et al. (April 2007). "Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro".The Journal of Pharmacology and Experimental Therapeutics.321(1): 116–127.doi:10.1124/jpet.106.116863.PMID17234900.S2CID578835.
  23. ^Liberles SD, Buck LB (August 2006). "A second class of chemosensory receptors in the olfactory epithelium".Nature.442(7103): 645–650.Bibcode:2006Natur.442..645L.doi:10.1038/nature05066.PMID16878137.S2CID2864195.
  24. ^abcBarak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, et al. (September 2008)."Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor".Molecular Pharmacology.74(3): 585–594.doi:10.1124/mol.108.048884.PMC3766527.PMID18524885.
  25. ^abcLam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (June 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1".Eur. J. Pharmacol.763(Pt B): 136–42.doi:10.1016/j.ejphar.2015.06.026.PMID26093041.
    TAAR1 peripheral and immune localization/functions: It is important to note that in addition to the brain, TAAR1 is also expressed in the spinal cord (Gozal et al., 2014) and periphery (Revel et al., 2012c). It has been shown that TAAR1 is expressed and regulates immune function in rhesus monkey leukocytes (Babusyte et al., 2013; Nelson et al., 2007; Panas et al., 2012). In granulocytes, TAAR1 is necessary for chemotaxic migration of cells towards TAAR1 agonists. In addition, TAAR1 signaling in B and T cells can trigger immunoglobulin and cytokine release, respectively (Babusyte et al., 2013). TAAR1 is also expressed in the islets of Langerhans, stomach and intestines based on LacZ staining patterns carried out on TAAR1-KO LacZ mice (Revel et al., 2012c). Interestingly, the administration of selective TAAR1 partial agonist RO5263397 reverses the side effect of weight gain observed with the antipsychotic olanzapine, indicating that peripheral TAAR1 signalling can regulate metabolic homeostasis (Revel et al., 2012b)....

    Monoamine transporters and SLC22A carrier subfamily transport TAAR1 ligand: Studies using the rhesus monkey TAAR1 have shown that this receptor interacts with the monoamine transporters DAT, SERT, and NET in HEK cells (Miller et al., 2005; Xie and Miller, 2007; Xie et al., 2007). It has been hypothesized that TAAR1 interaction with these transporters might provide a mechanism by which TAAR1 ligands can enter the cytoplasm and bind to TAAR1 in intracellular compartments. A recent study has shown that in rat neonatal motor neurons, trace-amine specific signalling requires the presence and function of the transmembrane solute carrier SLC22A but not that of monoamine transporters (DAT, SERT, and NET) (Gozal et al., 2014). Specifically, it was shown that addition of β-PEA, tyramine, or tryptamine induced locomotor like activity (LLA) firing patterns of these neurons in the presence of N-Methyl D-Aspartate. Temporally, it was found that the trace amine induction of LLA is delayed compared to serotonin and norepinephrine induced LLA, indicating the target site for the trace amines is not located on the plasma membrane and could perhaps be intracellular. Importantly, blocking of SLC22A with pentamidine abolished trace amine induced LLA, indicating that trace amine induced LLA does not act on receptors found on the plasma membrane but requires their transport to the cytosol by SLC22A for induction of LLA.
  26. ^abDinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, et al. (June 2015)."3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling".J. Mol. Endocrinol.54(3): 205–216.doi:10.1530/JME-15-0003.PMID25878061.Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/o signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.
  27. ^Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, et al. (2015). "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers".Eur Neuropsychopharmacol.25(11): 2049–2061.doi:10.1016/j.euroneuro.2015.08.011.PMID26372541.S2CID41667764.Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
  28. ^abcdZucchi R, Chiellini G, Scanlan TS, Grandy DK (December 2006)."Trace amine-associated receptors and their ligands".British Journal of Pharmacology.149(8): 967–978.doi:10.1038/sj.bjp.0706948.PMC2014643.PMID17088868.Other biogenic amines are present in the central nervous system at very low concentrations in the order of 0.1–10 nm, representing <1% of total biogenic amines (Berry, 2004). For these compounds, the term 'trace amines' was introduced. Although somewhat loosely defined, the molecules generally considered to be trace amines include para-tyramine, meta-tyramine, tryptamine, β-phenylethylamine, para-octopamine and meta-octopamine (Berry, 2004) (Figure 2).
  29. ^abXie Z, Miller GM (July 2009)."A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain".The Journal of Pharmacology and Experimental Therapeutics.330(1): 316–325.doi:10.1124/jpet.109.153775.PMC2700171.PMID19364908.
  30. ^Rickli A, Kopf S, Hoener MC, Liechti ME (July 2015)."Pharmacological profile of novel psychoactive benzofurans".British Journal of Pharmacology.172(13): 3412–3425.doi:10.1111/bph.13128.PMC4500375.PMID25765500.
  31. ^abWainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, et al. (January 2007). "Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1".The Journal of Pharmacology and Experimental Therapeutics.320(1): 475–485.doi:10.1124/jpet.106.112532.PMID17038507.S2CID10829497.Several series of substituted phenylethylamines were investigated for activity at the human TAAR1 (Table 2). A surprising finding was the potency of phenylethylamines with substituents at the phenyl C2 position relative to their respective C4-substituted congeners. In each case, except for the hydroxyl substituent, the C2-substituted compound had 8- to 27-fold higher potency than the C4-substituted compound. The C3-substituted compound in each homologous series was typically 2- to 5-fold less potent than the 2-substituted compound, except for the hydroxyl substituent. The most potent of the 2-substituted phenylethylamines was 2-chloro-β-PEA, followed by 2-fluoro-β-PEA, 2-bromo-β-PEA, 2-methoxy-β-PEA, 2-methyl-β-PEA, and then 2-hydroxy-β-PEA.
    The effect of β-carbon substitution on the phenylethylamine side chain was also investigated (Table 3). A β-methyl substituent was well tolerated compared with β-PEA. In fact, S-(–)-β-methyl-β-PEA was as potent as β-PEA at human TAAR1. β-Hydroxyl substitution was, however, not tolerated compared with β-PEA. In both cases of β-substitution, enantiomeric selectivity was demonstrated.
    In contrast to a methyl substitution on the β-carbon, an α-methyl substitution reduced potency by ~10-fold for d-amphetamine and 16-fold for l-amphetamine relative to β-PEA (Table 4). N-Methyl substitution was fairly well tolerated; however, N,N-dimethyl substitution was not.
  32. ^Galley G, Beurier A, Décoret G, Goergler A, Hutter R, Mohr S, et al. (2016)."Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists".ACS Med Chem Lett.7(2): 192–197.doi:10.1021/acsmedchemlett.5b00449.PMC4753552.PMID26985297.
  33. ^abRevel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, et al. (May 2011)."TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity".Proc. Natl. Acad. Sci. U.S.A.108(20): 8485–8490.Bibcode:2011PNAS..108.8485R.doi:10.1073/pnas.1103029108.PMC3101002.PMID21525407.
  34. ^Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velázquez-Sánchez C, Sotnikova TD, et al. (June 2012). "Trace Amine-Associated Receptor 1 Partial Agonism Reveals Novel Paradigm for Neuropsychiatric Therapeutics".Biol Psychiatry.72(11): 934–942.doi:10.1016/j.biopsych.2012.05.014.PMID22705041.S2CID27334223.
  35. ^Cichero E, Francesconi V, Casini B, Casale M, Kanov E, Gerasimov AS, et al. (November 2023)."Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays".Pharmaceuticals.16(11): 1632.doi:10.3390/ph16111632.PMC10674299.PMID38004497.
  36. ^"RG 7351".AdisInsight.Springer Nature Switzerland AG. 5 November 2023.Retrieved20 October2024.
  37. ^"Delving into the Latest Updates on RG-7351 with Synapse".Synapse.19 September 2024.Retrieved20 October2024.
  38. ^"RG 7410".AdisInsight.13 October 2015.Retrieved23 October2024.
  39. ^"Delving into the Latest Updates on RG-7410 with Synapse".Synapse.19 September 2024.Retrieved23 October2024.
  40. ^Gursahani H, Jolas T, Martin M, Cotier S, Hughes S, Macfadden W, et al. (2023). "Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion".CNS Spectrums.28(2): 222.doi:10.1017/S1092852923001396.ISSN1092-8529.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.
  41. ^Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, et al. (November 2009)."The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system".Proceedings of the National Academy of Sciences of the United States of America.106(47): 20081–20086.Bibcode:2009PNAS..10620081B.doi:10.1073/pnas.0906522106.PMC2785295.PMID19892733.
  42. ^Scarano N, Espinoza S, Brullo C, Cichero E (July 2024)."Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands".Int J Mol Sci.25(15): 8226.doi:10.3390/ijms25158226.PMC11312273.PMID39125796.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.
  43. ^Decker AM, Brackeen MF, Mohammadkhani A, Kormos CM, Hesk D, Borgland SL, et al. (April 2022)."Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist".ACS Chem Neurosci.13(7): 1082–1095.doi:10.1021/acschemneuro.2c00086.PMC9730857.PMID35325532.
  44. ^abEiden LE, Weihe E (January 2011)."VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse".Ann. N. Y. Acad. Sci.1216(1): 86–98.Bibcode:2011NYASA1216...86E.doi:10.1111/j.1749-6632.2010.05906.x.PMC4183197.PMID21272013.VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR)... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
  45. ^Sulzer D, Cragg SJ, Rice ME (August 2016)."Striatal dopamine neurotransmission: regulation of release and uptake".Basal Ganglia.6(3): 123–148.doi:10.1016/j.baga.2016.02.001.PMC4850498.PMID27141430.Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle.... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
  46. ^abLedonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (2011)."Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons".Frontiers in Systems Neuroscience.5:56.doi:10.3389/fnsys.2011.00056.PMC3131148.PMID21772817.inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
  47. ^abmct (28 January 2012)."TAAR1".GenAtlas.University of Paris.Retrieved29 May2014.
    "• tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)"
  48. ^Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014)."Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons".Neuron.83(2): 404–416.doi:10.1016/j.neuron.2014.05.043.PMC4159050.PMID25033183.AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate.... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
  49. ^Vaughan RA, Foster JD (September 2013)."Mechanisms of dopamine transporter regulation in normal and disease states".Trends Pharmacol. Sci.34(9): 489–496.doi:10.1016/j.tips.2013.07.005.PMC3831354.PMID23968642.AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
  50. ^Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP (March 2009)."International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature".Pharmacological Reviews.61(1): 1–8.doi:10.1124/pr.109.001107.PMC2830119.PMID19325074.
  51. ^abcLindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family".Trends Pharmacol. Sci.26(5): 274–281.doi:10.1016/j.tips.2005.03.007.PMID15860375.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]
  52. ^abSotnikova TD, Caron MG, Gainetdinov RR (August 2009)."Trace amine-associated receptors as emerging therapeutic targets".Mol. Pharmacol.76(2): 229–235.doi:10.1124/mol.109.055970.PMC2713119.PMID19389919.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.
  53. ^Berry MD (January 2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases".Rev Recent Clin Trials.2(1): 3–19.CiteSeerX10.1.1.329.563.doi:10.2174/157488707779318107.PMID18473983.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].
  54. ^Zhukov IS, Kubarskaya LG, Tissen IY, Kozlova AA, Dagayev SG, Kashuro VA, et al. (March 2020). "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.doi:10.1007/s10571-019-00721-4.PMID31399838.S2CID199511689.
  55. ^Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, et al. (February 2012)."Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia".Arthritis and Rheumatism.64(2): 584–593.doi:10.1002/art.33338.PMC3237946.PMID21905019.
  56. ^abRaab S, Wang H, Uhles S, Cole N, Alvarez-Sanchez R, Künnecke B, et al. (2016)."Incretin-like effects of small molecule trace amine-associated receptor 1 agonists".Mol Metab.5(1): 47–56.doi:10.1016/j.molmet.2015.09.015.PMC4703809.PMID26844206.
  57. ^Zhukov IS, Ptukha MA, Zolotoverkhaja EA, Sinitca EL, Tissen IY, Karpova IV, et al. (May 2022)."Evaluation of Approach to a Conspecific and Blood Biochemical Parameters in TAAR1 Knockout Mice".Brain Sciences.12(5): 614.doi:10.3390/brainsci12050614.PMC9139149.PMID35625001.

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