Oral Presentation 2014 International Biophysics Congress

Voltage-gated sodium channels: Structure and function and disease (#127)

Bonnie Ann Wallace 1
  1. Birkbeck College, University of London, London, UK

In excitable cells, the action potential initiation results from the opening of voltage-gated sodium channels. In humans, mutations in sodium channels produce neurological and cardiovascular diseases; therefore these channels represent key targets for development of pharmaceutical drugs. Sodium channels are also present in some prokaryotes, where they function in homeostasis, motility, and chemotaxis. All sodium channels undergo a series of conformational changes associated with their open, closed and inactivated functional states.

We determined the crystal structure of the open conformation of the NavMs bacterial sodium channel1. Comparisons between this structure and the structure of the closely-related NavAb channel in the closed state reveal the mechanism of channel gating. Using a combination of crystallography and spectroscopic methods (SRCD and DEER-EPR) and molecular dynamics calculations2,3, the structure of the C-terminal domain (not visible in any of the previous crystal structures, but critical for full functioning of the channel) has also been determined; its flexibility is compatible with an opening mechanism that does not destabilise the tetrameric cytoplasmic domain coiled-coiled bundle.

            Recently, we have shown that drugs which block eukaryotic sodium channels also bind to and block the NavMs channel.  Crystallographic, computational and electrophysiology methods have been used to determine the functional effects and locations of these blockers within the channel cavity.  Their binding sites have also been validated by mutational studies. The affinities of the drugs are remarkably similar for the NavMs and human Nav1.1 channels, information which is valuable for the design of more specific and selective drugs.

1McCusker et al  (2012) Nature Communications 3, 1102.

2Bagnéris et al (2013) Nature Communications 4:2645. 

3Ulmschneider et al (2013) Proc. Nat. Acad. Sci. USA 110, 6364-6369.

Supported by grants from the U.K. Biotechnology and Biological Sciences Research Council.