TAAR1

From Wikipedia, the free encyclopedia
  (Redirected from TAAR1 agonist)
Jump to: navigation, search
Trace amine associated receptor 1
Identifiers
Symbols TAAR1 ; TA1; TAR1; TRAR1
External IDs OMIM609333 MGI2148258 HomoloGene24938 IUPHAR: 364 ChEMBL: 5857 GeneCards: TAAR1 Gene
RNA expression pattern
PBB GE TAAR1 gnf1h10289 at tn.png
More reference expression data
Orthologs
Species Human Mouse
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 – 132.65 Mb
Chr 10:
23.92 – 23.92 Mb
PubMed search [1] [2]

Trace amine-associated receptor 1 (TAAR1) is a protein that in humans is encoded by the TAAR1 gene.[1] TAAR1 is an amine-activated Gs- and Gq-coupled G protein-coupled receptor (GPCR) that is located in several peripheral organs and circulating lymphocytes, as well as within the presynaptic membrane of monoamine neurons in the central nervous system (CNS).[2] TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al.[3][4] TAAR1 is one of 15 discovered trace amine-associated receptors, which are so named for their ability to bind low-concentration, endogenous monoamines called trace amines.[5][6] TAAR1 is a key regulator of brain monoamines,[5] and may also play some role in immune system function.[7]

Discovery[edit]

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.[3][4]

Structure[edit]

TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily.[4] It has 7 transmembrane domains with short N and C terminal extensions.[8] 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.[3] 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 a sets of 35 amino acids known to be involved directly in receptor-ligand interaction.[6]

Gene[edit]

All TAAR genes are located on a single chromosome spanning 109kb 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.[6]

Tissue distribution[edit]

To date, TAAR1 has been identified and cloned in four 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, and lungs, and at low levels in the brain amygdala.[3] 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 species. These regions include the dorsal and ventral caudate nucleus, putamen, substantia nigra, nucleus accumbens, ventral tegmental area, locus coeruleus, amygdala, and raphe nucleus.[2][9]

TAAR1 is the only TAAR subtype not found in the olfactory epithelium.[10]

Location within neurons[edit]

Human TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons;[5][11] in model cell systems, hTAAR1 has extremely poor membrane expression.[11] A method to induce hTAAR1 membrane expression has been used to study its pharmacology via a bioluminescence resonance energy transfer cAMP assay.[11]

Because TAAR1 is an intracellular receptor in monoamine neurons, TAAR1 ligands must enter the presynaptic neuron through a membrane transport protein[note 1] or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce reuptake inhibition and neurotransmitter efflux.[5] 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.[5] 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.[5] 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.

Ligands[edit]

Agonists[edit]

Trace amines and common biogenic monoamines[edit]

For a more comprehensive list, see Trace amine.

Trace amines are those found in 0.1-10 nM concentrations, constituting less than 1% of total biogenic amines in the mammalian nervous system.[12] The endogenous trace amines are para/meta-tyramine, tryptamine, phenylethylamine (PEA), and para/meta-octopamine. These share structural similarities with the three common monoamines: serotonin, dopamine, and 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 → histamine → serotonin → norepinephrine.[3][4][12] The EC50 values for cAMP production caused by p-tyramine and PEA binding events are 214 and 324 nM, respectively.[4] Dopamine and serotonin have a 5 to 25-fold lower potency than either p-tyramine or PEA.[6] The discrepancies in ligand potency may act to balance the differences in monoamine concentrations, common amines being less potent than trace amines.

Thyronamines[edit]

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[edit]

  • RO5166017 or (S)-4-[(ethylphenylamino)methyl]-4,5-dihydrooxazol-2-ylamine is a selective TAAR1 agonist without significant activity at other targets.[16]
  • RO5203648 and RO5263397 are highly selective TAAR1 partial agonists.[17] 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.[18]

Antagonists[edit]

  • EPPTB or N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide is a selective TAAR1 antagonist.[19]

Function[edit]

A dopamine neuron with co-localized TAAR1
v · t · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
Amphetamine or a trace amine enters the presynaptic neuron directly across the neuronal membrane or through DAT. Once inside, it binds to TAAR1. When activated, TAAR1 reduces dopamine receptor firing rate and triggers PKA and PKC signaling, resulting in DAT phosphorylation. Phosphorylated DAT then either operates in reverse (causing effluxion and reuptake inhibition) or withdraws into the presynaptic neuron and ceases transport.

Monoaminergic systems[edit]

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.[12] 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.[3][4][6] 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.[13] 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.[5] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[5] The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific.[5] 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.[5] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[5]

In neurons with co-localized TAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in the synaptic cleft, thereby heightening the response of the post-synaptic neuron.[5] Through direct activation of 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.[20][21][22] Amphetamine and trace amines can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[5] As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter.[5] Upon entering the presynaptic neuron, these compounds activate TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[5][23]

Immune system[edit]

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.[7] 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.[7] A recent paper showed that, along with TAAR1, TAAR2 is required for full activity of trace amines in PMN cells.[24]

Phytohaemagglutinin upregulates hTAAR1 mRNA in circulating leukocytes;[2] in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists.[2] TAAR1 agonists (specifically, trace amines) have also been shown to induce interleukin 4 secretion in T-cells and immunoglobulin E secretion in B cells.[2]

Clinical significance[edit]

Low phenethylamine (PEA) concentration in the brain is associated with major depressive disorder, and high concentrations are 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 [3][12]). 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 (see "Discussion" in [3][6]). 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. Interestingly, mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.[6]

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.[25]

TAAR1 activation has also been connected to activation of lymphocyte immuno-characteristics via a PKA and PKC phosphorylation.[7] In the future, problems with lymphocyte function may be reconciled by TAAR1 manipulation.

Research[edit]

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.[26] Unlike amphetamine, there is no evidence that cocaine is an agonist at TAAR1.

Notes[edit]

  1. ^ In dopamine, norepinephrine, and serotonin neurons, the primary membrane transporters are DAT, NET, and SERT respectively.[5]

References[edit]

  1. ^ "Entrez Gene: TAAR1 trace amine associated receptor 1". 
  2. ^ a b c d e Maguire JJ, Davenport AP (5 March 2015). "Trace amine receptor: TA1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved April 2015.
    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.
     
  3. ^ a b c d e f g h Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (July 2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 8966–71. doi:10.1073/pnas.151105198. PMC 55357. PMID 11459929. 
  4. ^ a b c d e f g h Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK (December 2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Mol. Pharmacol. 60 (6): 1181–8. doi:10.1124/mol.60.6.1181. PMID 11723224. 
  5. ^ a b c d e f g h i j k l m n o p Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468. 
  6. ^ a b c d e f g Lindemann 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): 372–85. doi:10.1016/j.ygeno.2004.11.010. PMID 15718104. 
  7. ^ a b c d Panas MW, Xie Z, Panas HN, Hoener MC, Vallender EJ, Miller GM (December 2012). "Trace amine associated receptor 1 signaling in activated lymphocytes". J Neuroimmune Pharmacol 7 (4): 866–76. doi:10.1007/s11481-011-9321-4. PMC 3593117. PMID 22038157. 
  8. ^ Xie Z, Miller GM (November 2009). "Trace amine-associated receptor 1 as a monoaminergic modulator in brain". Biochem. Pharmacol. 78 (9): 1095–104. doi:10.1016/j.bcp.2009.05.031. PMC 2748138. PMID 19482011. 
  9. ^ Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM (April 2007). "Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro". J. Pharmacol. Exp. Ther. 321 (1): 116–27. doi:10.1124/jpet.106.116863. PMID 17234900. 
  10. ^ Liberles SD, Buck LB (August 2006). "A second class of chemosensory receptors in the olfactory epithelium". Nature 442 (7103): 645–50. doi:10.1038/nature05066. PMID 16878137. 
  11. ^ a b c Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, Violin JD, Lefkowitz RJ, Caron MG, Gainetdinov RR (September 2008). "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor". Mol. Pharmacol. 74 (3): 585–94. doi:10.1124/mol.108.048884. PMC 3766527. PMID 18524885. 
  12. ^ a b c d Zucchi R, Chiellini G, Scanlan TS, Grandy DK (December 2006). "Trace amine-associated receptors and their ligands". Br. J. Pharmacol. 149 (8): 967–78. doi:10.1038/sj.bjp.0706948. PMC 2014643. PMID 17088868. 
  13. ^ a b Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". J. Pharmacol. Exp. Ther. 330 (1): 316–25. doi:10.1124/jpet.109.153775. PMC 2700171. PMID 19364908. 
  14. ^ Rickli A, Kopf S, Hoener MC, Liechti ME (2015). "Pharmacological profile of novel psychoactive benzofurans". Br. J. Pharmacol. 172 (13): 3412–25. doi:10.1111/bph.13128. PMID 25765500. 
  15. ^ a b Wainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, Nelson DL (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): 475–85. doi:10.1124/jpet.106.112532. PMID 17038507. 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.
     
  16. ^ Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc. Natl. Acad. Sci. U.S.A. 108 (20): 8485–90. doi:10.1073/pnas.1103029108. PMC 3101002. PMID 21525407. 
  17. ^ Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (June 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1". Eur. J. Pharmacol. doi:10.1016/j.ejphar.2015.06.026. PMID 26093041. 
  18. ^ Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velázquez-Sánchez C, Sotnikova TD, Morairty SR, Harmeier A, Groebke Zbinden K, Norcross RD, Bradaia A, Kilduff TS, Biemans B, Pouzet B, Caron MG, Canales JJ, Wallace TL, Wettstein JG, Hoener MC (June 2012). "Trace Amine-Associated Receptor 1 Partial Agonism Reveals Novel Paradigm for Neuropsychiatric Therapeutics". Biol Psychiatry 72 (11): 934–42. doi:10.1016/j.biopsych.2012.05.014. PMID 22705041. 
  19. ^ Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B (November 2009). "The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system". Proc. Natl. Acad. Sci. U.S.A. 106 (47): 20081–6. doi:10.1073/pnas.0906522106. PMC 2785295. PMID 19892733. 
  20. ^ Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc. Natl. Acad. Sci. U.S.A. 108 (20): 8485–8490. doi:10.1073/pnas.1103029108. PMC 3101002. PMID 21525407. 
  21. ^ Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Front Syst Neurosci 5: 56. doi:10.3389/fnsys.2011.00056. PMC 3131148. PMID 21772817. 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. 
  22. ^ mct (28 January 2012). "TAAR1". GenAtlas. University of Paris. Retrieved 29 May 2014.
     • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
     
  23. ^ 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". Pharmacol. Rev. 61 (1): 1–8. doi:10.1124/pr.109.001107. PMC 2830119. PMID 19325074. 
  24. ^ Babusyte A, Kotthoff M, Fiedler J, Krautwurst D (March 2013). "Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2". J. Leukoc. Biol. 93 (3): 387–94. doi:10.1189/jlb.0912433. PMID 23315425. 
  25. ^ Arthritis Rheum. 2011 Sep 8. doi: 10.1002/art.33338
  26. ^ Li JX (May 2014). "Trace Amines and Cocaine Abuse". ACS Chem Neurosci 5 (7): 497–8. doi:10.1021/cn500104s. PMID 24849494. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.