Molecules in the Serotonin-Melatonin Synthesis Pathway Have Distinct Interactions with Lipid Membranes

The neurotransmitter serotonin is involved in physiological processes such as appetite, sleep, and mood and diseases such as anxiety and depression. Traditionally, the effects of serotonin were thought to be initiated by binding to its target transmembrane receptors. It is also known that serotonin can bind directly to the membrane with high affinity and modulate lipid dynamics, lateral segregation of lipids, vesicular association, and membrane protein activity. We investigated if other small molecules in the serotonin metabolic pathway, some of which are known to be signaling molecules while some others are not, have similar membrane modulating effects. Therefore, we examined serotonin and several of its metabolites: 5-hydroxytryptophan (5-HTP), serotonin, <i>N</i>-acetylserotonin (NAS), and melatonin in model membranes mimicking synaptic membranes. Using ²H NMR spectroscopy of deuterated 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC), we observed that all metabolites disorder the synaptic membrane-mimicking model membranes. The largest disordering effect was observed for NAS and the smallest for tryptophan. Using fluorescence correlation spectroscopy, it was found that only NAS promotes vesicular association similar to that of serotonin, while the others did not. Furthermore, we found that the serotonin metabolites differed in their membrane distribution by employing solid state ¹H magic angle spinning nuclear Overhauser enhancement spectroscopy (NOESY) experiments in simple POPC membranes. Similar results were obtained in synaptic membrane mimics using molecular dynamics simulations. In conclusion, while the causal correlation between membrane modulation effects and membrane distribution for the serotonin metabolites remains elusive, this study suggests that small-molecule metabolites and drugs can have drastic biological effects mediated through the membrane. The finding that small changes in structure lead to very different membrane modulation and distributions suggests the possibility of developing membrane modulating drugs in the future.