Molecular Dynamics of Trace Amine Transport through Neuronal Membranes

Abstract

The trace amines are a family of endogenous compounds, synthesized in neurons, for whom a family of receptor proteins has been identified. Unlike neurotransmitter receptors, trace amine receptors do not appear to be expressed at the plasma membrane of cells, rather remaining in the cytosol. This requires trace amines readily cross the lipid bilayer in order to interact with the receptor and effect signal tranduction. It has previously been assumed that this occurs via passive diffusion. However, the unknown rate of passive diffusion in allowing trace amines to cross the synaptic cleft has hindered the progress of recent studies attempting to determine their physiological role (M.D. Berry, J. Neurochem, 90, 257-271, (2004), A. G. Ianculescu et al, Endocrinology, 150, 1991 (2009)). Molecular dynamics (MD) simulations have been carried out to determine the position dependent diffusion constant, D(z),and the Potential of Mean Force (PMF) of several trace amines both inside and outside the membrane. From this data, the trace amine flux through the membrane can be calculated. Using specialized free energy simulation techniques, MD trajectories have been generated and analyzed to determine the mean force exerted on the trace amines, 2-phenylethylamine (2PE), its protonated form, 2PE+ and on 3-iodothyronomine, at distances ranging from 20 angstrom right to the middle of a symmetric sphingomyelin membrane. Preliminary results indicate a potential barrier ∼13 Kcal/mol for 2PE+ and ∼20Kcal/mol for 2PE. These relatively high potential barriers are consistent with a very low transmembrane flux due to passive diffusion. The contribution this information makes to the question of yet-undiscovered transporters for trace amines is discussed in the conclusions.