Ion Channels: Proepileptic Effects of BK Channel Gene Mutations

The textbooks tell us that the opening of sodium and calcium channels depolarize cells and increase excitability, whereas potassium and chloride channels repolarize membrane potentials and reduce excitability. Mostly this generalization is true, and therefore the drugs that block voltage-dependent sodium and calcium channels, such as phenytoin and lamotrigine, are effectively utilized as anticonvulsants and anti-epileptic drugs. Similarly, agonists for ionotropic GABA receptors (that conduct chloride ions), such as benzodiazepines, are used to control seizures. More recently, new classes of potassium channel agonists were developed for a similar purpose. But the role of individual potassium channels is more complex than described by such simple concepts. Surprisingly, there are examples where inhibition of BK-type potassium channels reduce excitability of neurons. A recent finding has shown that a human gain-of-function mutation in the BK potassium channel gene results in epilepsy. Such a finding indicates that this channel, and perhaps other potassium channels, has much more complex roles than described in textbooks. This article will discuss our current understanding of these channels and propose some hypotheses to explain the paradoxical, pro-epileptic effects of BK potassium channels.