Comparison of membrane permeabilities of trace amines and corresponding neurotransmitters
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Trace amines (2-phenylethylamine, p-tyramine, p-octopamine and tryptamine) are endogenous compounds structurally similar to the monoamine neurotransmitters and distributed throughout the nervous systems of vertebrates. However, they are not thought to be stored in synaptic vesicles, nor released in an activity-dependent manner. Their synthesis, however, is regulated with the enzyme aromatic L-amino acid decarboxylase being a rate limiting factor. Distinct post-synaptic effects of trace amines have been demonstrated and a family of G-protein-coupled Trace Amine-Associated Receptors (TAAR) has been identified. The TAAR protein, though, is poorly translocated to the cell membrane and remains intracellular. Hence, in order to bind to post-synaptic TAAR, trace amines have to cross cell membranes. This was previously thought to occur by simple diffusion. Recent computer simulations have, however, predicted a high-energy barrier associated with this process. Here the membrane passage of trace amines in the absence of transporters has been measured directly for the first time using the Fluorosome system. The trace amines tyramine (p<0.01), and tryptamine (p<0.001), had significantly greater membrane permeability than the comparable monoamine neurotransmitters, with trace amine permeability half-lives under 15 seconds. The effect of membrane transporters on the permeability of a representative trace amine (tyramine) and neurotransmitter (dopamine) was examined in Caco-2 and synaptosome studies. Tyramine accumulation (≈7-8% of administered concentration) was approximately twice that of dopamine (3-4%) in Caco-2 cells. Equilibration of both tyramine and dopamine occurred in less than 10 minutes. In synaptosomes both tyramine and dopamine uptake equilibrated within 1 minute. Tyramine release from synaptosomes was significantly faster (p<0.001) than that of dopamine. Dopamine release in depolarized membranes was significantly faster (p<0.01, F = 6.95) while tyramine release was significantly slower (p< 0.05, F = 5.86) than in non-depolarized membranes. Release from synaptosomes was significantly slower than Fluorosome membrane passage for both tyramine (p<0.0002, F = 13.63) and dopamine (p<0.0001, F = 56.77) indicating the involvement of processes other than simple diffusion. In conclusion, the trace amines are more permeable than the corresponding neurotransmitters both in the absence and presence of transporters.
DegreeMaster of Science (M.Sc.)
SupervisorDr.Berry, Mark D.
CommitteeDr.Alcorn, Jane; Dr. Mousseau, Darrell D.; Dr. Pietrock, Michael; Dr. Wickstrom, Mark
Copyright DateJune 2012
permeability coefficients, diffusion half lives