Weak interactions of neurotransmitters and the lipid matrix in the synaptic membrane have been hypothesized to play a role in synaptic transmission of nerve signals, particularly with respect to receptor desensitization (Cantor, R. S. Biochemistry 2003, 42, 11891). The strength of such interactions, however, was not measured, and this is an obvious impediment for further evaluation and understanding of a possible role for desensitization. We have used dialysis equilibrium to directly measure the net affinity of selected neurotransmitters for lipid membranes and analyzed this affinity data with respect to calorimetric measurements and molecular dynamics simulations. We studied an anionic (glutamate), a cationic (acetylcholine), and two zwitterionic (γ-aminobutyric acid and glycine) neurotransmitters, and membranes of pure dimyristoyl phosphatidylcholine (DMPC), DMPC doped with 10% anionic lipid (dimyristoyl phosphatidylglycerol, DMPG, or dimyristoyl phosphatidylserine, DMPS), or 1:1 mixtures of dipalmitoyl phosphatidylcholine (DPPC) and dilauroyl phosphatidylcholine (DLPC). The results showed a remarkable variability among the investigated systems. For example, the chloride salt of acetylcholine interacts unfavorably with DMPC and is thus preferentially excluded from the membrane's hydration layer. Conversely, the zwitterionic neurotransmitters are attracted to membranes with 10% anionic lipid and their local concentration at the interface is 5-10 times larger than in the aqueous bulk. The simulations suggest that this attraction mainly relies on electrostatic interactions of the amino group of the neurotransmitter and the lipid phosphate. We conclude that moderate attraction to lipid membranes occurs for some polar neurotransmitters and hence that one premise for a theory of bilayer-mediated modulation of nerve transmission seems to be fulfilled. However, the strong variability in interaction strengths also shows that this attraction is not an inherent property of all neurotransmitters.
