Abstract
ABSTRACTAlcohol addiction ranks among the leading global causes of preventable death and disabilities in human population. Understanding the sites of ethanol action that mediate its acute and chronic neural and behavioural effects is critical to develop appropriate treatment options for this disorder. The N-methyl-d-asparate (NMDA) receptors are ligand-gated heterotetrameric ion channels, which are known to directly interact with alcohol in a concentration-dependent manner. Yet, the exact molecular mechanisms and conformational dynamics of this interaction are not well understood. Here, we conducted a series of molecular dynamics simulations of the interaction of moderate ethanol concentrations with rat's wild-type GluN1–GluN2B NMDA Receptor under physiological conditions. The simulations suggest that glutamate or glycine alone induce an intermediate conformational state and point towards the transmembrane domain (TMD) as the site of action of ethanol molecules. Ethanol interacts by double hydrogen bonds with Trp635 and Phe638 at the transmembrane M3 helix of GluN2B. Alcohol not only reduces the pore radius of the ion channel within the TMD but also decreases accessibility of glutamate and glycine to the ligand-binding sites by altering the structure of the ligand-binding domain and significantly widening the receptor in that area.
Highlights
Alcohol intake induces a multi-scale spectrum of spatiotemporal effects, the underlying neurobiology and physiology of which are not yet completely understood.Among a variety of proteins as primary sites of action of ethanol in the central nervous system, the ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor represents the most prominent target [1,2,3,4]
The NMDA receptor is a ligand- and voltage-gated ion channel that is in general an assembly of GluN1, GluN2 (A–D) and GluN3 subunits forming heterodimers with the twofold symmetry axis running through the entire molecule composed of an amino terminal domain (ATD), a ligandbinding domain (LBD) and a transmembrane domain (TMD)
The results suggest the appropriateness of molecular dynamics (MD) simulations to pursue this question, as they are in agreement with previous experimental studies identifying sites of action of glutamate and glycine at these receptors
Summary
Alcohol intake induces a multi-scale spectrum of spatiotemporal effects, the underlying neurobiology and physiology of which are not yet completely understood.Among a variety of proteins as primary sites of action of ethanol in the central nervous system, the ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor represents the most prominent target [1,2,3,4]. A number of studies have focused on the identification of the molecular locus of alcohol action on NMDA receptors, within the membraneassociated (M) domains of GluN1 and GluN2 subunits. Thereby, substitutions of phenylalanine (F637 and F639) at M3 of GluN1 subunit [16,17,18] as well as tyrosine T822, methionine M823 and alanine A825 of the GluN2 subunit [19,20] have been shown to influence the sensitivity of NMDA receptor to ethanol. Despite the value of these investigations, their search strategies have been hypothesis-driven and site directed as a precise description of the complete structure of NMDA receptor including the M-domains was not available until recently [21,22]. The relationship between the ethanol interaction and the conformational dynamics of the receptor [23,24] is still missing
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