Abstract
Recent determination of the crystal structures of bacterial voltage-gated sodium (NaV) channels have raised hopes that modeling of the mammalian counterparts could soon be achieved. However, there are substantial differences between the pore domains of the bacterial and mammalian NaV channels, which necessitates careful validation of mammalian homology models constructed from the bacterial NaV structures. Such a validated homology model for the NaV1.4 channel was constructed recently using the extensive mutagenesis data available for binding of μ-conotoxins. Here we use this NaV1.4 model to study the ion permeation mechanism in mammalian NaV channels. Linking of the DEKA residues in the selectivity filter with residues in the neighboring domains is found to be important for keeping the permeation pathway open. Molecular dynamics simulations and potential of mean force calculations reveal that there is a binding site for a Na+ ion just inside the DEKA locus, and 1–2 Na+ ions can occupy the vestibule near the EEDD ring. These sites are separated by a low free energy barrier, suggesting that inward conduction occurs when a Na+ ion in the vestibule goes over the free energy barrier and pushes the Na+ ion in the filter to the intracellular cavity, consistent with the classical knock-on mechanism. The NaV1.4 model also provides a good description of the observed Na+/K+ selectivity.
Highlights
Voltage-gated sodium (NaV) channels enable fast and selective permeation of Na+ ions across membranes of excitable cells, and thereby play critical roles in electrical signaling in the nervous system, heart and muscles [1]
This is consistent with electronegativity arguments based on the total charge of −e at the DEKA locus, which would be neutralized by the +e charge of a Na+ ion
We have investigated ion permeation properties of a NaV1.4 homology model, which was previously validated using the mutagenesis data for binding of μ-conotoxins
Summary
Voltage-gated sodium (NaV) channels enable fast and selective permeation of Na+ ions across membranes of excitable cells, and thereby play critical roles in electrical signaling in the nervous system, heart and muscles [1]. Dysfunctional NaV channels are implicated in various disorders, which makes them potential drug targets for their treatment [2]. A molecular-level understanding the operation of NaV channels is an important problem in physiology with ramifications in medicine and pharmacology. For this reason, numerous experimental studies of NaV channels have been conducted to decipher the structure-function relations [1, 3]. High-affinity toxin ligands have been used to probe the pore domain of NaV and pinpoint the positions of functionally important residues [4,5,6,7,8,9,10,11]. In the absence of any crystal structures, it was difficult to uniquely interpret such data and obtain unambiguous structural information
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