期刊
BIOCHIMIE
卷 203, 期 -, 页码 40-50出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2022.04.006
关键词
Serotonin; Sphingomyelin; Lipid phase separation; Solid state NMR; Lipid -drug interactions
资金
- Deutsche Forschungsgemeinschaft (CRC) [1423, 421152132, A04]
- Department of Atomic Energy, Government of India [RTI4003]
- Magnus Ehrnrooth foundation
- Ruth and Nils-Erik Stenback's Foundation
- Kazan Federal University [0671-2020-0051]
- German Academic Exchange Services (DAAD) in the Michael Lomonosov Program [57515327]
This study investigates the modulation of lipid membrane phase behavior by serotonergic drugs. The findings suggest that these drugs increase the hydrophobic mismatch between lipid phases, resulting in larger domain sizes. Furthermore, the presence of these drugs alters the membrane's order and mechanical properties. These findings provide insights into the side effects observed for serotonergic and other clinically relevant drugs.
Serotonin is an endogenous neurotransmitter involved in both physiological and pathophysiological processes. Traditionally, serotonin acts as a ligand for G protein-coupled receptors (GPCRs) leading to subsequent cell signaling. However, serotonin can also bind to lipid membranes with high affinity and modulate the phase behavior in 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC)/N-palmitoyl-D-erythro-sphingosylphosphorylcholine (PSM)/cholesterol model membranes mimicking the outer leaflet of the plasma membrane. Here, we investigated if serotonergic drugs containing the pharmacophore from serotonin would also modulate phase behavior in lipid membranes in a similar fashion. We used 2H NMR spectroscopy to explore the phase behavior of POPC/PSM/cholesterol (4/4/2 molar ratio) mixtures in the presence of the serotonergic drugs aripiprazole, BRL-54443, BW-723C86, and CP-135807 at a lipid to drug molar ratio of 10:1. POPC and PSM were perdeuterated in the palmitoyl chain, respectively, and prepared in individual samples. Numerical lineshape simulations of the 2H NMR spectra were used to calculate the order parameter profiles and projected lengths of the saturated acyl chains. All serotonergic drugs induce two components in 2H NMR spectra, indicating that they increased the hydrophobic mismatch between the thickness of the coexisting lipid phases leading to larger domain sizes, relatively similarly to serotonin. AFM force indentation and Raman spectral studies, which interrogate membrane mechanical properties, also indicate changes in membrane order in the presence of these drugs. These findings highlight how serotonergic drugs alter membrane phase behavior and could modulate both target and other membrane proteins, possibly explaining the side effects observed for serotonergic and other clinically relevant drugs.(c) 2022 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.
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