Potassium channel double drugs

Hyperexcitability diseases, such as epilepsy, pain, and cardiac arrhythmia, are all in need of better treatments.

Voltage-gated ion channels are attractive targets for pharmaceuticals, but one problem is that it has been difficult to make high affinity activators which are selective.

The overarching goal of the proposed project is to identify completely new pathways to modulate voltage-gated ion channels. We will use several electrophysiological techniques including automated patch clamp.

The specific aims are to (i) explore channel gating of the brain’s important M-type potassium channel: To find out (a) why this channel is expressed as heterotetramers, (b) how many voltage sensors are required to activate to open the channel, and (c) which functional roles epilepsy-causing mutations have. (ii) To develop new types of drugs: To (a) construct and evaluate compounds based on our previous predictions, (b) explore how two or more drugs in combination can lead to better potency and selectivity, and (c) link two compounds together to create new high affinity compounds – the double drug idea. (iii) Explore cellular excitability: To do in silico modelling to (a) develop new kinetic models for ion channel gating and to calculate excitability in different cell types, and (b) find out which specific steps in channel gating that should be affected by pharmaceuticals to alter excitability most effectively.

To (c) develop and test compounds that specifically act on the steps in (iii-b).