BBB seminar: Bonnie Wallace
Molecular mechanisms of voltage-gated sodium channels in health and disease
Institute of Structural and Molecular Biology, Birkbeck College, University of London, UK
Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with the activation and opening of these channels resulting in the initial phase of the action potential. Different but highly homologous isoforms are found in CNS, PNS, and cardiac tissues; they are thus important key targets for the development of antiepileptic, analgesic, anaesthetic, and antiarrhythmic drugs.
I will discuss our structure-function studies on the prokaryotic NavMs channel (a close homologue of human sodium channels) that have enabled visualisation of the locations of the binding sites of channel-blocking drugs, the ions present in the channel selectivity filter, mutations associated with different disease states, and the transmembrane fenestrations that enable drugs ingress into their binding sites in the channel central cavity. Our high resolution crystal structures, combined with spectroscopic, mutational, electrophysiological, and molecular dynamics studies of the channels in different functional states have also revealed the changes in the voltage sensor and the channel gate associated with ion transport and channel opening and closing, and form the basis for design of novel state-dependent pharmaceutical drugs.
Chairperson: Petri Kursula, Department of Biomedicine