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On conduction in a bacterial sodium channel.

ABSTRACT: Voltage-gated Na?-channels are transmembrane proteins that are responsible for the fast depolarizing phase of the action potential in nerve and muscular cells. Selective permeability of Na? over Ca²? or K? ions is essential for the biological function of Na?-channels. After the emergence of the first high-resolution structure of a Na?-channel, an anionic coordination site was proposed to confer Na? selectivity through partial dehydration of Na? via its direct interaction with conserved glutamate side chains. By combining molecular dynamics simulations and free-energy calculations, a low-energy permeation pathway for Na? ion translocation through the selectivity filter of the recently determined crystal structure of a prokaryotic sodium channel from Arcobacter butzleri is characterised. The picture that emerges is that of a pore preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers. In contrast to K?-channels, the movements of the ions appear to be weakly coupled in Na?-channels. When the free-energy maps for Na? and K? ions are compared, a selective site is characterised in the narrowest region of the filter, where a hydrated Na? ion, and not a hydrated K? ion, is energetically stable.

SUBMITTER: Furini S

PROVIDER: S-EPMC3320569 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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On conduction in a bacterial sodium channel.

Furini Simone S Domene Carmen C

PLoS computational biology 20120405 4

Voltage-gated Na⁺-channels are transmembrane proteins that are responsible for the fast depolarizing phase of the action potential in nerve and muscular cells. Selective permeability of Na⁺ over Ca²⁺ or K⁺ ions is essential for the biological function of Na⁺-channels. After the emergence of the first high-resolution structure of a Na⁺-channel, an anionic coordination site was proposed to confer Na⁺ selectivity through partial dehydration of Na⁺ via its direct interaction with conserved glutamate ...[more]

PMID: 22496637

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Project description:Striking structural differences between voltage-gated sodium (Nav) channels from prokaryotes (homotetramers) and eukaryotes (asymmetric, four-domain proteins) suggest the likelihood of different molecular mechanisms for common functions. For these two channel families, our data show similar selectivity sequences among alkali cations (relative permeability, Pion/PNa) and asymmetric, bi-ionic reversal potentials when the Na/K gradient is reversed. We performed coordinated experimental and computational studies, respectively, on the prokaryotic Nav channels NaChBac and NavAb. NaChBac shows an "anomalous," nonmonotonic mole-fraction dependence in the presence of certain sodium-potassium mixtures; to our knowledge, no comparable observation has been reported for eukaryotic Nav channels. NaChBac's preferential selectivity for sodium is reduced either by partial titration of its highly charged selectivity filter, when extracellular pH is lowered from 7.4 to 5.8, or by perturbation-likely steric-associated with a nominally electro-neutral substitution in the selectivity filter (E191D). Although no single molecular feature or energetic parameter appears to dominate, our atomistic simulations, based on the published NavAb crystal structure, revealed factors that may contribute to the normally observed selectivity for Na over K. These include: (a) a thermodynamic penalty to exchange one K(+) for one Na(+) in the wild-type (WT) channel, increasing the relative likelihood of Na(+) occupying the binding site; (b) a small tendency toward weaker ion binding to the selectivity filter in Na-K mixtures, consistent with the higher conductance observed with both sodium and potassium present; and (c) integrated 1-D potentials of mean force for sodium or potassium movement that show less separation for the less selective E/D mutant than for WT. Overall, tight binding of a single favored ion to the selectivity filter, together with crucial inter-ion interactions within the pore, suggests that prokaryotic Nav channels use a selective strategy more akin to those of eukaryotic calcium and potassium channels than that of eukaryotic Nav channels.

Dataset Information

On conduction in a bacterial sodium channel.

Publications

On conduction in a bacterial sodium channel.

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