title: Binding of serotonin to lipid membranes.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) is a prevalent neurotransmitter throughout the animal kingdom. It exerts its effect through the specific binding to the serotonin receptor, but recent research has suggested that neural transmission may also be affected by its nonspecific interactions with the lipid matrix of the synaptic membrane. However, membrane-5-HT interactions remain controversial and superficially investigated. Fundamental knowledge of this interaction appears vital in discussions of putative roles of 5-HT, and we have addressed this by thermodynamic measurements and molecular dynamics (MD) simulations. 5-HT was found to interact strongly with lipid bilayers (partitioning coefficient ~1200 in mole fraction units), and this is highly unusual for a hydrophilic solute like 5-HT which has a bulk, oil-water partitioning coefficient well below unity. It follows that membrane affinity must rely on specific interactions, and the MD simulations identified the salt-bridge between the primary amine of 5-HT and the lipid phosphate group as the most important interaction. This interaction anchored cationic 5-HT in the membrane interface with the aromatic ring system pointing inward and a prevailing residence between the phosphate and the carbonyl groups of the lipid. The unprotonated form of 5-HT shows the opposite orientation, with the primary amine pointing toward the membrane core. Partitioning of 5-HT was found to decrease lipid chain order. These distinctive interactions of 5-HT and model membranes could be related to nonspecific effects of this neurotransmitter.
authors: Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark. ghp@kemi.dtu.dk
authors: Günther H
authors: GH
authors: Peters
authors: Chunhua
authors: C
authors: Wang
authors: Nicolaj
authors: N
authors: Cruys-Bagger
authors: Gustavo F
authors: GF
authors: Velardez
authors: Jesper J
authors: JJ
authors: Madsen
authors: Peter
authors: P
authors: Westh
mesh_terms: D001665:Binding Sites; D008051:Lipid Bilayers / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D012701:Serotonin / Q000737:chemistry*
chemical_list: D008051:Lipid Bilayers; D012701:Serotonin