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

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.