A safety valve for nerve conduction

A major step forward in understanding how sodium channels function has been made by a team of researchers at the London Centre for Nanotechnology (LCN), the Institute of Structural and Molecular Biology (a joint venture between Birkbeck College and UCL), Harvard University and Microsoft Research.

Voltage-gated sodium channels have essential roles in electrical signaling, allowing the passage of charged ions across the cell membrane in response to action potentials. Whilst previous crystal structures of bacterial sodium channels have revealed the nature of their transmembrane regions, these studies have been unable to address the question of the biological role of their flexibly tethered domains.

In this work a combination of electron paramagnetic resonance (EPR) spectroscopy, x-ray crystallography, and molecular dynamics simulations were used to establish that the structure of the carboxy-terminal domain of the NavMs channel from the prokaryote Magnetococcus marinus includes a flexible region linking the transmembrane domains to a four-helix coiled-coil bundle.

Electrophysiological experiments also demonstrated that the coiled-coil domain couples inactivation with channel opening, and that this switch is modulated by negatively charged residues in the linker region. This new and unexpected behavior suggests a wider role for flexibly tethered, stable domains in the control of channel closing as ‘oscillators’, stabilizing the open state and allowing correct ion flow.

Dr Chris Kay, who together with Professor Bonnie Wallace at Birkbeck led the study, commented that multi-disciplinary approaches to complex problems, combining diverse techniques such as EPR spectroscopy, simulation and crystallography, have truly come of age.

Journal link: Role of the C-terminal domain in the structure and function of tetrameric sodium channels.  Nature Communications 4, 2465

DOI: doi:10.1038/ncomms3465

Figure: EPR-derived model showing the dynamics of the pore and C-terminal domain

LCN Author(s): 
Other contributors: 
Claire Bagnéris, Paul G. DeCaen, Benjamin A. Hall, Claire E. Naylor, David E. Clapham & B. A. Wallace