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Theoretical Studies of the M2 Transmembrane Segment of the Glycine Receptor: Models of the Open Pore Structure and Current-Voltage Characteristics

Mary Hongying Cheng ^*, Michael Cascio   and Rob D. Coalson ^* 

^* Department of Chemistry, and Molecular Biophysics Program, University of Pittsburgh, Pittsburgh, Pennsylvania 15260; and Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Correspondence: Address reprint requests to Michael Cascio, E-mail: cascio{at}pitt.edu.

The pentameric glycine receptor (GlyR), a member of the nicotinicoid superfamily of ligand-gated ion channels, is an inhibitory Cl^– channel that is gated by glycine. Using recently published NMR data of the second transmembrane segment (M2) of the human 1 GlyR, structural models of pentameric assemblies embedded in a lipid bilayer were constructed using a combination of experimentally determined constraints coupled with all-atom energy minimization. Based on this structure of the pentameric M2 "pore", Brownian dynamics simulations of ion permeation through this putative conducting open state of the channel were carried out. Simulated I-V curves were in good agreement with published experimental current-voltage curves and the anion/cation permeability ratio, suggesting that our open-state model may be representative of the conducting channel of the full-length receptor. These studies also predicted regions of chloride occupancy and suggested residues critical to anion permeation. Calculations of the conductance of the cation-selective mutant A251E channel are also consistent with experimental data. In addition, both rotation and untilting of the pore helices of our model were found to be broadly consistent with closing of the channel, albeit at distinct regions that may reflect alternate gates of the receptor.

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