A renaissance in trace amines inspired by a novel GPCR family

https://doi.org/10.1016/j.tips.2005.03.007Get rights and content

Trace amines (TAs) are endogenous compounds that are related to biogenic amine neurotransmitters and are present in the mammalian nervous system in trace amounts. Although their pronounced pharmacological effects and tight link to major human disorders such as depression and schizophrenia have been studied for decades, the understanding of their molecular mode of action remained incomplete because of the apparent absence of specialized receptors. However, the recent discovery of a novel family of G-protein-coupled receptors (GPCRs) that includes individual members that are highly specific for TAs indicates a potential role for TAs as vertebrate neurotransmitters or neuromodulators, although the majority of these GPCRs so far have not been demonstrated to be activated by TAs. The unique pharmacology and expression pattern of these receptors make them prime candidates for targets in drug development in the context of several neurological diseases. Current research focuses on dissecting their molecular pharmacology and on the identification of endogenous ligands for the apparently TA-insensitive members of this receptor family.

Section snippets

Trace amines find their receptors

The classical biogenic amines [serotonin (5-HT), noradrenaline, adrenaline, dopamine and histamine] have important roles as neurotransmitters in the central and peripheral nervous systems [1]. Their synthesis and storage, in addition to their degradation and reuptake after release, are tightly regulated, and an imbalance in the levels of biogenic amines is known to be responsible for altered brain function in many pathological conditions 2, 3, 4, 5. A second class of endogenous amine compounds,

Molecular properties of trace amine-associated receptors

All mammalian TAARs analyzed to date share several molecular properties [15]. All except one TAAR gene [TAAR2 (GPR58)] are single-exon encoded, locate to a narrow region of ∼100–200 kb of a single chromosome and have coding sequences of ∼1 kb in length. The total number of genes and the proportion of intact genes compared with the proportion of pseudogenes differ substantially between species: there are 19 (including 2 pseudogenes) and 16 (including 1 pseudogene) TAAR genes in rat and mouse

Trace amine metabolism and pharmacology

TAs (β-PEA, p-tyramine, octopamine and tryptamine) are all primary amines generated directly by enzymatic decarboxylation of their respective precursor amino acids or, in the case of octopamine, via additional conversion by dopamine β-hydroxylase (DBH) (Figure 2). TAs are metabolized to biologically inactive degradation products predominantly via monoamine oxidase (MAO) with different selectivities for the MAO-A or MAO-B subtype. As a result of the rapid turnover rate of TAs, the endogenous

TAARs as potential drug targets for the treatment of psychiatric disorders

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

Outlook and future perspectives

The identification of specific receptors has always been key to the understanding of the biological function and pharmacology of any transmitter-like biological compound, as the example of histamine illustrates well: when the importance of amine-mediated systems emerged in the 1960s, it was only after the identification of specific receptors that histamine was generally accepted as an established neurotransmitter 56, 57. Likewise, it is only the recent identification of TAARs, some of which

Acknowledgements

We would like to thank our colleagues M. Ebeling, N.A. Kratochwil, J-L. Moreau, H. Stalder, S. Kolczewski, E. Borroni, J.G. Wettstein, A.J. Sleight and D.K. Grandy for many stimulating discussions. We acknowledge the continued support by F. Hoffmann-La Roche.

References (60)

  • A.Y. Deutch et al.

    Neurotransmitters

  • M.L. Wong et al.

    Research and treatment approaches to depression

    Nat. Rev. Neurosci.

    (2001)
  • A. Carlsson

    Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence

    Annu. Rev. Pharmacol. Toxicol.

    (2001)
  • P. Tuite et al.

    Recent developments in the pharmacological treatment of Parkinson's disease

    Expert Opin. Investig. Drugs

    (2003)
  • F.X. Castellanos et al.

    Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes

    Nat. Rev. Neurosci.

    (2002)
  • T.A. Branchek et al.

    Trace amine receptors as targets for novel therapeutics: legend, myth and fact

    Curr. Opin. Pharmacol.

    (2003)
  • R.T. Premont

    Following the trace of elusive amines

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • D.D. Mousseau et al.

    A high-affinity [3H] tryptamine binding site in human brain

    Prog. Brain Res.

    (1995)
  • J.K. McCormack

    Autoradiographic localization of tryptamine binding sites in the rat and dog central nervous system

    J. Neurosci.

    (1986)
  • L.E. Dyck

    Release of some endogenous trace amines from rat striatal slices in the presence and absence of a monoamine oxidase inhibitor

    Life Sci.

    (1989)
  • E.M. Parker et al.

    Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding

    J. Pharmacol. Exp. Ther.

    (1988)
  • B. Borowsky

    Trace amines: identification of a family of mammalian G protein-coupled receptors

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • J.R. Bunzow

    Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor

    Mol. Pharmacol.

    (2001)
  • L. Lindemann

    Trace amine associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors

    Genomics

    (2005)
  • O. Civelli

    GPCR deorphanizations: the novel, the known and the unexpected transmitters

    Trends Pharmacol. Sci.

    (2005)
  • T.S. Scanlan

    3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone

    Nat. Med.

    (2004)
  • M.D. Berry

    Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators

    J. Neurochem.

    (2004)
  • M.V. Olson et al.

    Sequencing the chimpanzee genome: insights into human evolution and disease

    Nat. Rev. Genet.

    (2003)
  • P. Malherbe

    Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine

    Mol. Pharmacol.

    (2003)
  • J.M. Saavedra

    β-Phenylethylamine, phenylethanolamine, tyramine and octopamine

  • J.M. Saavedra

    The distribution and properties of the nonspecific N-methyltransferase in brain

    J. Neurochem.

    (1973)
  • J.M. Saavedra

    Localisation of phenylethanolamine N-methyl transferase in the rat brain nuclei

    Nature

    (1974)
  • R.S. Jones et al.

    Tryptamine and 5-hydroxytryptamine: actions and interactions of cortical neurones in the rat

    Life Sci.

    (1980)
  • R.S. Jones

    Tryptamine modifies cortical neurone responses evoked by stimulation of nucleus raphe medianus

    Brain Res. Bull.

    (1982)
  • M.D. Berry

    The effects of administration of monoamine oxidase-B inhibitors on rat striatal neurone responses to dopamine

    Br. J. Pharmacol.

    (1994)
  • Federici, M. et al. Trace amines depress GABAB response in dopaminergic neurons by inhibiting GIRK channels. Mol....
  • X.M. Li

    Absence of 2-phenylethylamine binding after monoamine oxidase inhibition in rat brain

    Eur. J. Pharmacol.

    (1992)
  • R.L. Hauger

    Specific [3H] beta-phenylethylamine binding sites in rat brain

    Eur. J. Pharmacol.

    (1982)
  • A. Vaccari

    High affinity binding of [3H]-tyramine in the central nervous system

    Br. J. Pharmacol.

    (1986)
  • Cited by (0)

    View full text