# Influence of Lipid Composition on Nonspecific Interactions of Serotonin with Model Membranes

## TL;DR

This study explores how serotonin interacts with different model membranes, showing that it changes membrane properties, which could affect brain function and drug effects.

## Contribution

The study reveals serotonin's nonspecific effects on lipid membranes and how these effects vary with membrane composition.

## Key findings

- Serotonin increases water permeability and reduces bilayer tension in lipid membranes.
- Serotonin modifies phase transition behavior and lipid conformational ordering.
- Membrane sensitivity to serotonin is highest in DOPC/DOPS and DOPC/Sphingomyelin/Cholesterol mixtures.

## Abstract

Serotonin is a monoamine
neurotransmitter, which plays an important
role in the development and functioning of the central nervous system.
Recent biophysical studies reveal that nonspecific interactions between
serotonin and lipid membranes significantly alter lipid bilayer properties,
impacting synaptic function and plasticity. To better understand these
critical interactions and their broader implications for neural function
and pharmacology, we investigated the interactions of serotonin (at
concentrations ranging from 1 to 40 mM) with model membranes prepared
as droplet interface bilayers, liposomes, and supported bilayers.
These membrane systems comprised single, binary, and ternary lipid
mixtures, including pure DOPC, DOPC/DOPS (10:1 mol ratio), and DOPC/Sphingomyelin/Cholesterol
(1:1:0.2 mol ratio). Our analysis employing various experimental techniques
shows that the interaction of serotonin with lipid membranes of diverse
compositions has overall nonspecific effects in (1) influencing the
barrier properties of the lipid membrane, as demonstrated by increased
water permeability compared to the control; (2) modifying the phase
transition behavior, evidenced by decrease in the main phase transition
temperature and reduction of the transition enthalpy; (3) perturbing
the conformational ordering of lipid membranes, as indicated by the
increase in specific Raman intensity ratio; and (4) reducing bilayer
tension with increasing serotonin concentrations. Overall, membrane
modifications increase with rising serotonin concentrations, plateauing
at higher levels. Sensitivity to serotonin varies by lipid composition
in the order: DOPC/DOPS ≈ DOPC/Sphingomyelin/Cholesterol >
DOPC. Our experimental findings reveal that serotonin significantly
alters membrane properties, particularly affecting neuronal membrane
composition and lipid rafts, which are critical for membrane protein
organization and signaling. These findings suggest that serotonergic
drugs and pathological fluctuations in serotonin may influence signaling
not only through classical receptor-mediated pathways, but also by
altering the lipid–protein landscape of the membrane, with
potential implications for drug efficacy, off-target effects, and
the development of therapies that target membrane composition in serotonin-related
disorders.