Abstract
p-Tyramine is an archetypal member of the endogenous family of monoamines known as trace amines, and is one of the endogenous agonists for trace amine-associated receptor (TAAR)1. While much work has focused on the function of TAAR1, very little is known about the regulation of the endogenous agonists. We have previously reported that p-tyramine readily crosses lipid bilayers and that its release from synaptosomes is non-exocytotic. Such release, however, showed characteristics of modification by one or more transporters. Here we provide the first characterization of such a transporter. Using frontal cortical and striatal synaptosomes we show that p-tyramine passage across synaptosome membranes is not modified by selective inhibition of either the dopamine, noradrenaline or 5-HT transporters. In contrast, inhibition of uptake-2 transporters significantly slowed p-tyramine re-uptake. Using inhibitors of varying selectivity, we identify Organic Cation Transporter 2 (OCT2; SLC22A2) as mediating high affinity uptake of p-tyramine at physiologically relevant concentrations. Further, we confirm the presence of OCT2 protein in synaptosomes. These results provide the first identification of a high affinity neuronal transporter for p-tyramine, and also confirm the recently described localization of OCT2 in pre-synaptic terminals.
Highlights
Exocytosis, consistent with simple diffusion across the lipid bilayer
The identification of a family of vertebrate G protein-coupled receptors, at least some of which are selectively activated by 2-phenylethylamine and p-tyramine[3,4], has catalyzed a resurgence of interest in the so-called trace amines. While this has led to notable advances in elucidating the pharmacology and physiology of TAAR1, there is still a relative lack of understanding about the homeostatic mechanisms in place to regulate the endogenous ligands
The activity of the synthetic enzyme amino acid decarboxylase (AADC) is known to be regulated in response to dopaminergic[53,54,55] and noradrenergic[56] receptor activation, an effect that alters the rate of synthesis of 2-phenylethylamine[57], but not dopamine[58,59]
Summary
Exocytosis, consistent with simple diffusion across the lipid bilayer. Under such a situation synaptic levels of trace amines would be in a steady state, controlled solely by the relative rates of synthesis and degradation. A number of known transporter proteins have been reported to include trace amines in their substrate profile, this has rarely been examined at physiologically-relevant, nanomolar levels. Such transporters can be broadly classified as neuronal and extraneuronal, definitions which generally correspond to the uptake-1 and uptake-2 concept originally proposed by Iverson[27]. With respect to neuronal monoamines, uptake-2 transporters are typified by the Organic Cation Transporter (OCT; Slc22A1-3) family of transporters and Plasma Membrane Monoamine Transporter (PMAT; Slc29A4) These are thought of as polyspecific, low-selectivity, high capacity transporters that mediate overflow clearance of synaptic neurotransmitters when uptake-1 transporters become saturated[34]. OCT241,43,44, OCT342,45 and PMAT46,47 have all been reported to be expressed in neurones
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