Mechanistic insights into xenon inhibition of NMDA receptors from MD simulations.
Inhibition of N-methyl-D-aspartate (NMDA) receptors has been viewed as a primary cause of xenon anesthesia, yet the mechanism is unclear. Here, we investigated interactions between xenon and the ligand-binding domain (LBD) of a NMDA receptor and examined xenon-induced structural and dynamical changes that are relevant to functional changes of the NMDA receptor. Several comparative molecular dynamics simulations were performed on two X-ray structures representing the open- and closed-cleft LBD of the NMDA receptor. We identified plausible xenon action sites in the LBD, including those nearby agonist sites, in the hinge region, and at the interface between two subunits. The xenon-binding energy varies from -5.3 to -0.7 kcal/mol. Xenon's effect on the NMDA receptor is conformation-dependent and is produced through both competitive and noncompetitive mechanisms. Xenon can promote cleft opening in the absence of agonists and consequently stabilizes the closed channel. Xenon can also bind at the interface of two subunits, alter the intersubunit interaction, and lead to a reduction of the distance between two GT linkers. This reduction corresponds to a rearrangement of the channel toward a direction of pore size decreasing, implying a closed or desensitized channel. In addition to these noncompetitive actions, xenon was found to weaken the glutamate binding, which could lead to low agonist efficacy and appear as competitive inhibition.
Liu
Lu Tian
LT
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
Xu
Yan
Y
Tang
Pei
P
D000777:Anesthetics / Q000378:metabolism / Q000494:pharmacology*; D030562:Databases, Protein; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014978:Xenon / Q000378:metabolism / Q000494:pharmacology*
D000777:Anesthetics; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D014978:Xenon