Science Week: Structures of sodium channels

This post was contributed by Dr Clare Sansom, of Birkbeck’s Department of Biological Sciences.

The structures of sodium channels and what they can teach us about human health, particularly rare neurological diseases, were explained during Science Week.

Professor Bonnie Wallace, of Birkbeck’s Department of Biological Sciences, delivered the fascinating and accessible lecture on 18 April. She has been at Birkbeck for about twenty years and now directs the department’s impressive research work on the structural biology of membrane ion channels.  Membrane proteins are ubiquitous, are responsible for the transport of both chemicals and signals into and out of cells, and form some of the most important drug targets. They are also, as Professor Wallace made very clear in her talk, some of the most challenging of all proteins for structural biologists to examine.

All cell membranes are semi-permeable, which means that some substances can pass across them easily while others are excluded. Ions, which are charged, are generally excluded by the hydrophobic (“water hating”) membranes. This could be something of a problem, as ion transport into and out of cells is an essential physiological process. Ion channels are evolution’s solution to this problem: proteins embedded in membranes that allow ions to selectively enter and leave cells.

Much of Professor Wallace’s work over the last 10 years has focused on the structures of voltage gated sodium channels. These open to allow sodium ions to enter cells, and close to prevent them from doing so, in response to changes in potential across the membrane, and they are found throughout nature. Small molecules can bind to these channels, holding them either open or closed; some of these are severely toxic, but others are important drugs for cardiac arrhythmias, epilepsy, and pain.

It took over ten years for Professor Wallace and her group to isolate the gene, clone and purify the protein, obtain crystals and finally solve the structure of the channel pore. The structure was finally solved using the powerful X-rays generated at Diamond, the UK’s only synchrotron radiation source located near Harwell in Oxfordshire.

Different structural forms
These channels exist in three different structural forms: “open”, “closed” and “inactivated”. Many years before the detailed structures were solved Professor Wallace and her group had used a biophysical technique, circular dichroism (CD) spectroscopy, to examine the conformational changes that occurred when mammalian and bacterial channels switched from one state to the other. As always, however, the full atomic-crystal structures yielded very much more information.

Professor Wallace and her group were the first to solve the structure of an open form of the channel which showed the “top” part of this structure, towards the extracellular membrane surface, has a hydrophobic surface, and an internal selectivity filter which allows sodium ions in while keeping others, including potassium and calcium ions, out.  The lower part, on the extracellular surface, is where the ions exit. This open structure could be compared with the published structure of closed form of the channel, and showed that the upper portion containing the selectivity filter was virtually unchanged The conformational change associated with opening and closing the channel occurs at the internal or cytoplasmic side of the protein. When the pore closes, a small turning motion of the “bottom” part of the helical bundle causes the bottom ends of the pore to come together and the diameter of the pore to shrink; the resulting channel is too small for sodium ions to pass through, so any inside the pore become trapped there.

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Bacterial  voltage gated sodium channels have a domain at the C-terminal end of the molecule that is necessary for channel activity but that was not visible in any of the crystal structures. Professor Wallace and her group looked at this part of the molecule using a particularly powerful form of CD spectroscopy called synchrotron radiation CD spectroscopy that she had pioneered, and showed that each subunit had an extremely flexible protein chain separating the pore from a C-terminal helix. Using this information, the group have proposed a novel mechanism for channel opening in which the conformational change in the pore is enabled by these helices oscillating up and down.

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Two subunits of the bacterial sodium channel pore in the “open” conformation, shown as a ribbon structure

Implications for health
The final part of Professor Wallace’s talk was devoted to the role of sodium channels in health and disease, and as a drug target. A few unfortunate individuals have mutations in a type of channel that is involved in the response to painful stimuli. If this channel is jammed open, patients experience a constant, burning pain termed erythromelalgia, most commonly in their hands and feet. Professor Wallace showed that an equivalent mutation from phenylalanine to valine at the base of one of the protein subunits could cause the channel to open just enough for ions to pass through. There are also people in whom these channels are jammed in the closed position or are missing altogether, and they feel no pain, even if they walk on hot coals. It may one day be possible for drugs based on our knowledge of these structures to be designed to ease both these conditions.


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