Structure and Function of the Human 1.8 Voltage-Gated Sodium Channel Associated with Pain Sensation

Voltage-gated sodium channels play essential roles in the process of signal conduction in nervous tissues. The human sodium channel (isoform 8) is primarily found in the peripheral nervous system, and in the healthy organism is responsible for pain sensation. Mutations in it cause a range of diseases, including chronic pain and certain types of multiple sclerosis. The aim of this project is to determine the three-dimensional structure of this protein (and its complexes with drugs and naturally-occuring toxins), and relate these structures to its functional properties and conformational changes which result from mutations associated with different disease states. These studies will not only provide information on the molecular basis of these diseases but also aid in the development of new pharmaceutical drugs that specifically target this channel type, leading to fewer side-effects due to adventitious interactions with other channels.

Voltage-gated sodium channels play essential roles in the process of neurotransmission, with the initial phase of the action potential arising from conformational changes associated with their activation and opening. The human sodium channel isoform 8 (hNav1.8) is primarily found in dorsal root ganglion neurons and in the healthy organism is responsible for pain sensation. Mutations in it are causally related to a range of diseases, including chronic pain and certain types of multiple sclerosis. The aim of this project is to determine the first three-dimensional structure of the hNav1.8 protein (and its complexes with ligands, including natural toxins) using cryo-electron microscopy and/or crystallography, and relate these structures to its electrophysiological properties and conformational changes resulting from mutations associated with different disease states. These studies will not only inform on the molecular basis of these diseases but also aid in the development of new pharmaceutical drugs that specifically target this channel type, being potent whilst selective, thus producing fewer side-effects due to adventitious interactions with other channels.

There are important potential impacts of this research both for public health and for the economy, because human sodium channels (hNavs) are essential proteins required for functioning of the healthy human organism, including pain perception. Sodium channels play critical roles in excitable tissue and are linked to many disease states. Hence, knowledge of their structure and function will benefit both the public (enhancing quality of life and productivity), and the commercial private sector (aiding in the rational development of new pharmaceuticals).
The pharmaceutical market for specific and highly efficacious sodium channel inhibitors/modulators is enormous, because the potential number of people with either chronic or acute pain is vast. It is for this reason that big pharma, as well as many smaller biotech companies, have active programmes for the development of sodium channel-targeting drugs. The availability of the structures of hNav1.8 (the isoform primarily located in the peripheral nervous system and DRG neurons that is associated with chronic and inflammatory pain) both alone and in complex with ligands, along with associated functional characterisations, should have a dramatic impact on the initial and refinement phases of new drug design. In addition to hNav1.8-specific drugs, the high level of homology of hNav1.8 to other hNav isoforms whose misfunctioning produce a wide range of other neurological and cardiovascular diseases, means that drug discovery programmes targeting the other isoforms should also benefit from the availability of hNav1.8 drug/channel complex structures: they will enable comparative modelling studies to better ensure specific targeting of treatments without side effects resulting from less specific, broad-based sodium channel inhibitors. Consequently, as an essential aspect of "quality of life" is the ability to live pain-free, information leading to the development of hNav1.8-specific drugs to treat chronic pain, should ultimately directly impact on the quality of life of the general public.