RESEARCH

Theme 1: Modulation of voltage-gated potassium channels for the treatment of epilepsy

Epilepsy is a diverse collection of neurological disorders characterized by abnormal electrical activity in the brain leading to seizures. An estimated 50 million people worldwide are affected by some form of epilepsy, and startlingly, 30% of affected individuals are resistant to conventional treatments. We are investigating the detailed mechanism of action of a new class of anti-epileptic drug. Retigabine is the prototypical member of this class, and over the past few years has been approved for use in humans in Europe and North America. Retigabine has a unique mechanism of action: it is the only anti-epileptic drug that activates voltage-gated K+ channels in the brain. We investigate the molecular target of retigabine (KCNQ channels, or ‘M’-channels), and other drugs that are thought to target the voltage-sensing domain of these channels. We hope this work will accelerate the development of new anti-epileptic drugs, and develop our understanding of how mutations in these channels are linked to seizure disorders.

Theme 2: Ion channel regulation in multi-protein complexes

Mutations in the Kv1.2 potassium channel gene have been linked to severe epileptic encephalopathy, highlighting the essential role of this channel in the regulation of electrical activity. We use this as a model system to investigate assembly of ion channels into multi-protein complexes. We recently identified Slc7a5 (LAT1) as a powerful regulator of Kv1.2 expression and activity. This is of great interest to us, because mutations in both Kv1.2 and Slc7a5 are linked to neurological diseases, and manyl epilepsy-linked Kv1.2 mutations exhibit hypersensitivity to the effects of Slc7a5. We are also actively investigating a number of other regulatory mechanisms identified from unbiased mass spectrometry screens of voltage-gated potassium channel complexes. We hope this work will reveal unrecognized complexity in the organization and regulation of ion channels involved in signal transmission in the brain.