Ion channel function and modulation in human disease

Ion channels are an essential class of proteins that underlie rapid signaling, sensation, and movement in our bodies. These proteins form pores in cell membranes that allow charged ions to pass through and create tiny electrical currents that control cellular activity. Our research program investigates how changes in the function of certain ion channels can lead to diseases, or be targeted to treat certain diseases.

Theme 1: Modulation of voltage-gated potassium channels in 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 as it is the only anti-epileptic drug that activates voltage-gated K+ channels in the brain. The molecular target of retigabine (KCNQ channels, or ‘M’-channels) provide an interesting system to investigate ion channel function and pharmacology, and are an important target for the development of new anti-epileptic drugs.

We are also investigating a poorly understood mechanism of ‘use-dependent activation’ of Kv1.2-containing neuronal potassium channels. This mechanism allows potassium channels to adapt their behavior in response to repetitive stimulation, and this may influence how certain neurons respond to the extreme electrical activity that occurs during a seizure. Interestingly, mutations in the Kv1.2 potassium channel gene have been recently linked to severe epileptic encephalopathy, highlighting the essential role of this channel in the regulation of electrical activity.

Theme 2: Genetic forms of diabetes caused by altered electrical activity of pancreatic β-cells.

Appropriate release of insulin in response to ingestion of a meal is also controlled by ion channels. In pancreatic β-cells, an important ion channel class named KATP (because they are regulated by intracellular ATP:ADP) control cellular excitability in response to changes in the metabolic state. Mutations in these channels can lead to inheritable forms of diabetes (too little insulin secretion) or hyperinsulinism (too much insulin secretion). We carry out detailed investigations of the regulation of KATP channels and the effects of commonly used anti-diabetic drugs on these channels.

Methods and approaches used in the lab:

We employ diverse approaches to study the detailed function and pharmacology of a variety of ion channels. Trainees in the lab develop expertise in unique approaches including unnatural amino acid mutagenesis and voltage clamp fluorometry, along with conventional electrophysiology techniques and a significant exposure to molecular biology. The combination of these methods allows us to identify fundamental details of ion channel function and regulation by drugs.