The presence of the so-called trace amines 2-phenylethylamine, m-tyramine, p-tyramine, m-octopamine, p-octopamine and tryptamine in the mammalian central nervous system has been known for several decades. Despite much initial interest, these amines have largely been thought of as little more than metabolic by-products. The recent description of a family of mammalian trace amine receptors has, however, seen a resurgence of interest in the physiological role of this class of compounds. Although the trace amines are well documented to cause amphetamine-like effects, such responses only occur at concentrations multiple orders of magnitude above normal physiological levels. As such, it seems unlikely that these responses reflect the true physiological role of the trace amines. In this article previous studies showing responses to physiologically relevant concentrations of trace amines are reviewed, along with those showing a reciprocal relationship between trace amine levels and fluctuations in basal monoaminergic tone. On the basis of these studies it is hypothesized that the trace amines function as endogenous neuromodulators of classical monoamine neurotransmitters. These effects are seen as an altered neuronal sensitivity to monoamine neurotransmitters, with no change in neuronal excitability in the absence of neurotransmitter.

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The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.

Human inherited cataract is both clinically diverse and genetically heterogeneous. Here we report the identification of the first mutations affecting the major intrinsic protein of the lens, MIP, encoded by the gene MIP on 12q14. MIP is a member of the aquaporin family of membrane-bound water channels. The mutations identified are predicted to disturb water flux across the lens cell membrane.

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Classically, aromatic L-amino acid decarboxylase (AADC) has been regarded as an unregulated, rather uninteresting enzyme. In this review, we describe advances made during the past 10 years, demonstrating that AADC is regulated both pre- and post-translation. The significance of such regulatory mechanisms is poorly understood at present, but the presence of tissue specific control of expression raises the real possibility of AADC being involved in processes other than neuro-transmitter synthesis. We further discuss clinical and physiological situations in which such regulatory mechanisms may be important, including the intriguing possibility of AADC gene regulation being linked to that of factors thought to have a role in apoptosis and its prevention.

Mining of the human genome has revealed approximately 7000 novel proteins, which could serve as potential targets for the development of novel therapeutics. Of these, approximately 2000 are predicted to be G-protein coupled receptors. Within this group of proteins, a family of 18 mammalian receptors has recently been identified that appear to exhibit selectivity toward the so-called trace amines. The trace amines are a family of endogenous compounds with strong structural similarity to classical monoamine neurotransmitters, consisting primarily of 2-phenylethylamine, m- and p-tyramine, tryptamine, m- and p-octopamine and the synephrines. The endogenous levels of these compounds are at least two orders of magnitude below those of neurotransmitters such as dopamine, noradrenaline and 5-HT. The effects of these low physiological concentrations have been difficult to demonstrate but it has been suggested that they may serve to maintain the neuronal activity of monoamine neurotransmitters within defined physiological limits. Such an effect of trace amines would make them ideal candidates for the development of novel therapeutics for a wide range of human disorders. Although the demonstration of a trace amine family of receptors has seen a resurgence of interest in these endogenous compounds, with recent articles reviewing trace amine pharmacological and physiological responses, the potential clinical utility of the trace amine receptors has not been specifically addressed. Historically, trace amines have been implicated in a diverse array of human pathologies ranging from schizophrenia to affective disorders to migraine. Recent studies have strengthened some of this historical data by linking trace amine receptor polymorphisms and mutations to distinct clinical conditions. The aim of the current article is to review the previous studies linking trace amines to human pathology in the context of the recently discovered trace amine receptors and evidence of the existence of trace amine receptor polymorphisms and mutations associated with such disorders. In addition, recent evidence linking trace amines to the development of drug dependence will be discussed.