Channeling a Neuron's Excitability

Like people, neurons sometimes need to be steadied a bit, so that they don't overreact to stimuli. Helping to keep neurons in check are potassium channels, tiny pores that allow potassium ions to flow out of the cells. In today's Science, researchers describe two proteins that together make up a potassium channel called the M-channel. Knowing the channel's components will help scientists learn what turns it on and off and could lead to new drugs for epilepsy or Alzheimer's disease.

Over the years, researchers have identified 20 or so types of potassium channels and the proteins that make up most of them. But the proteins that form the M-channel had remained elusive, even though scientists were keen to lay their hands on them to help understand the important regulator of nerve excitability. By letting positively charged potassium ions flow out of nerve cells, the M-channel makes it harder for them to fire, thus reducing their excitability.

David McKinnon and Jane Dixon of the State University of New York, Stony Brook, and their colleagues were able to find the M-channel proteins by taking advantage of the fact that some neurons contain the channels, while others lack them. The researchers compared RNA messages in the two types of cells to find out which of the known potassium channel proteins they were making. They found a key difference: KCNQ2, a protein that had not previously been linked to any known channel, was made only in M-channel-containing cells. This indicated that it could be part of the M-channel, which the researchers confirmed by injecting RNA encoding the different KCNQ subunits into frog egg cells. They found that KCNQ2 combines with another subunit, KCNQ3, to make a channel that behaves exactly like the M-channel.

The discovery will help researchers understand how neural excitation is controlled, and it may aid the development of drugs for neurological diseases such as epilepsy and Alzheimer's. In previous work, researchers had discovered that defects in the genes encoding KCNQ2 and KCNQ3 cause a hereditary form of epilepsy. By reducing neuronal excitability, a drug that enhanced M-currents might be an effective antiepileptic drug, says DuPont neuroscientist Barry Brown, a co-author on the paper. And M-channels are found in the hippocampus, where neural responsiveness can affect learning and memory. Several compounds developed as memory enhancers for Alzheimer's patients have already turned out to block the M-current.