Unusual Robustness of Neurotransmitter Vesicle Membranes against Serotonin-Induced Perturbations

Nature confines hundreds of millimolar of amphiphilic neurotransmitters, such as serotonin, in synaptic vesicles. This appears to be a puzzle, as the mechanical properties of lipid bilayer membranes of individual major polar lipid constituents of synaptic vesicles [phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS)] are significantly affected by serotonin, sometimes even at few millimolar concentrations. These properties are measured by atomic force microscopy, and their results are corroborated by molecular dynamics simulations. Complementary 2H solid-state NMR measurements also show that the lipid acyl chain order parameters are strongly affected by serotonin. The resolution of the puzzle lies in the remarkably different properties displayed by the mixture of these lipids, at molar ratios mimicking those of natural vesicles (PC:PE:PS:Cholesterol = 3:5:2:5). Bilayers constituting of these lipids are minimally perturbed by serotonin, and show only a graded response at physiological concentrations (>100 mM). Significantly, the cholesterol (up to 33% molar ratio) plays only a minor role in dictating these mechanical perturbations, with PC:PE:PS:Cholesterol = 3:5:2:5 and 3:5:2:0 showing similar perturbations. We infer that nature uses an emergent mechanical property of a specific mixture of lipids, all individually vulnerable to serotonin, to appropriately respond to physiological serotonin levels.

Automated summary

Nature confines high concentrations of amphiphilic neurotransmitters like serotonin in synaptic vesicles, which affect the mechanical properties of lipid bilayer membranes. However, a mixture of specific lipids in natural vesicles, mimicking their ratios, is minimally perturbed by serotonin, suggesting an emergent mechanical property of these lipids. The role of cholesterol in dictating the mechanical perturbations is minor, indicating that nature utilizes a specific lipid mixture's vulnerability to serotonin to appropriately respond to physiological levels.