Old drugs learn new tricks: insights from mammalian trace amine receptors.

Biogenic amines are important neuromodulators whose discovery laid the foundation of modern neuropharmacology. These compounds (which include norepinephrine, dopamine, serotonin, and histamine) are stored in secretory vesicles located in the cytoplasm, are released into the extracellular space by regulated exocytosis, then activate specific G protein-coupled receptors (GPCRs) located in preand postsynaptic plasma membranes of target neurons. The synthesis of biogenic amines from precursor amino acids involves a series of enzymatic reactions and active transport of the products of these reactions into regulated secretory vesicles. Once they have undergone exocytosis, biogenic amines are cleared rapidly from the extracellular space, both by uptake into the cytoplasm via distinct amine transporters located in the plasma membrane and by enzymatic metabolism occurring in the extracellular space and cytoplasm (Cooper et al., 1986; Nestler et al., 2001). Many of the enzymes, transporters, and receptors involved in the complex biology of biogenic amines have been characterized in great detail, suggesting the possibility that there is little left to be learned in this oldest area of neuropharmacology. Two recent studies, one reported in Proceedings of the National Academy of Sciences of the United States of America (Borowsky et al., 2001) and another in this issue of Molecular Pharmacology (Bunzow et al., 2001), demonstrate clearly that this is not the case. These studies identify a new family of GPCRs that are potently activated by a subset of so-called “trace amines”. Trace amines refer to a number of additional products of amino acid metabolism, as well as intermediates in the synthesis of “classical” biogenic amines, that are present in relatively large amount in neural tissue. Trace amines have been of interest for many years (Usdin et al., 1976; Boulton, 1985), particularly because substantial alterations in the amount of trace amines present in neural tissue are associated with pathological conditions (O’Reilly and Davis, 1994). However, the physiological effects of trace amines have remained obscure, as noted by Borowsky et al. (2001) and discussed in additional detail in a commentary accompanying that article (Premont et al., 2001). Thus the discovery of mammalian trace amine receptors by Borowsky et al. (2001) and Bunzow et al. (2001) is of fundamental physiological interest. The study by Bunzow et al. (2001) is of particular interest to pharmacologists because it suggests that trace amine receptors may sense major extracellular metabolites of the classical catecholamines dopamine, norepinephrine, and epinephrine. Moreover, the results of Bunzow et al. (2001) suggest that an old and extremely important class of therapeutic and abused drugs, the amphetamines [and related psychostimulant drugs, such as 3,4-methylenedioxymethamphetamine (“ecstasy”)], can directly activate trace amine receptors. Borowsky et al. (2001) and Bunzow et al. (2001) used different strategies, applying degenerate polymerase chain reaction to identify candidate GPCRs sharing sequence homology with serotonin or catecholamine receptors, respectively. These approaches led to the isolation of genomic and cDNA clones encoding a putative GPCR that was called the TA1 receptor because, when expressed in heterologous cells (in which coupling to Gs was observed), this receptor was activated with nanomolar potency by certain trace amines (tyramine, -phenylethylamine, and tryptamine) but not by “classical” biogenic amines such as dopamine and serotonin. Borowsky et al. (2001) performed reduced stringency screening and phylogenetic analysis suggesting that the TA1 receptor represents one member of two related subfamilies of mammalian GPCRs. Therefore, considerable subtype diversity may exist in this class of GPCRs. The mapping of trace amine receptor genes near a previously proposed susceptibility locus for schizophrenia (Cao et al., 1997), as noted by both groups, has interesting implications that merit further study.