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, N-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.