title: Modeling interactions between blocking and permeant cations in the NavMs channel.
abstract: Mechanisms of sodium channel block by local anesthetics (LAs) are still a matter of intensive studies. In the absence of high-resolution structures of eukaryotic channels, atomic details of LA-channel interactions are analyzed using homology modeling. LAs are predicted to access the closed channel through a sidewalk (fenestration) between the channel repeats, bind in a horizontal orientation, and leave its aromatic moiety in the interface. Recent X-ray structure of a bacterial sodium channel NavMs with a cationic molecule Pl1, which is structurally similar to LAs, has confirmed this theoretical prediction and demonstrated a reduced selectivity filter occupancy by the permeant ions in the Pl1-bound channel. However, the nature of the antagonism between LAs and permeant ions is still unclear. Here we used the NavMs structure and Monte Carlo energy minimizations to model Pl1 binding. Our computations predict that Pl1 can displace permeant ion(s) from the selectivity filter by both steric and electrostatic mechanisms. We hypothesize that the electrostatic mechanism is more general, because it is applicable to many LAs and related drugs, which lack a moiety capable to enter the selectivity filter and sterically displace the permeant ion. The electrostatic mechanism is also consistent with the data that various cationic blockers of potassium channels bind in the inner pore without entering the selectivity filter.
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russian Federation.
authors.forename: Vyacheslav S
authors.initials: VS
authors.lastname: Korkosh
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russian Federation; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Boris S
authors.initials: BS
authors.lastname: Zhorov
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russian Federation. Electronic address: denistikhonov2002@yahoo.com.
authors.forename: Denis B
authors.initials: DB
authors.lastname: Tikhonov
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D010539:Permeability; D011485:Protein Binding; D017433:Protein Structure, Secondary; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D026941:Sodium Channel Blockers; D015222:Sodium Channels
keywords: Ion channel block; Local anesthetics; Mechanism of action; Sodium channels