By David N. Leff
Sudden death is a salient symptom of a rare genetic heart ailment called Romano-Ward syndrome. Among cardiologists, this drastic disease is more descriptively known as "long QT interval."
"That naming feature," explained microbiologist and electrophysiologist David McKinnon, "describes the duration of the cardiac action potential, which is the electrical spark-like event in the ventricular myocytes of the long QT heart. The action potential," he went on, "is involved in problems of repolarization.
"Patients with long QT syndrome," McKinnon said, "are susceptible to cardiac arrhythmias under emotional or physical stress. "It's a relatively severe, but a relatively rare, genetic disease, with five-year survival of carriers after adolescence about 50 percent. Actually, long QT is not always that severe; you can have it and not really know it. Then, the first symptom would be death." (See BioWorld Today, March 19, 1998, p. 1 and Aug. 24, 1995, p. 1.)
At the heart of the QT disorder is a mutated potassium channel in the cells governing the heart's pumping action. A somewhat similar mutation accounts for a form of epilepsy that strikes newborn babies. Its official moniker is BFNC, standing for "benign familial neonatal convulsions."
Epilepsy Is Like 'Fibrillation In The Brain'
McKinnon, an associate professor of neurobiology at the State University of New York, Stony Brook, ascribes neonatal epilepsy to over-excited brain cells in the hippocampus and other regions. Here, too, mutations in the genes that express the proteins comprising potassium-ion channels are to blame.
He compared the epileptic neuronal excitation to the ventricular fibrillation of long QT in the heart. "By analogy," McKinnon observed, "one might call it fibrillation in the brain."
This makes itself known, typically on day three after a baby is born, with spasmodic twitching of limbs that comes and goes. "These clonic convulsions," he said, "tend to go away for good in a few weeks or months, so probably what's happening is that a second electrical current is coming in, and helping to damp down the neuronal excitability."
But not all BFNC babies are then out of the woods. About 13 percent of them will contract adult epileptic seizures in later life. So the search is on to find the genes that go wrong and make defective potassium channels. (See BioWorld Today, Dec. 30, 1997, p. 1.)
McKinnon is senior author of a paper in today's Science, dated Dec. 4, 1998, titled "KCNQ2 and KCNQ3 potassium channel subunits: Molecular correlates of the M-channel."
The subunits in question are the two proteins that co-assemble to form the doughnut-shaped channels, through the pores of which potassium ions flow in and out of cells — in this case, neurons. "KC" stands for "potassium channel."
These particular ones come in three persuasions, KCNQ1, 2 and 3. "The interesting thing about this gene family," McKinnon told BioWorld Today, "is that all three members' mutations cause problems in electroexcitability linked to genetic diseases. KCNQ1 relates to that cardiac long QT syndrome. Mutations in the other two reduce the M-current, and result in epilepsy."
That crucial M-current, McKinnon explained, "is an electrophysiological current that's involved in controlling the excitability of neurons over long time periods — in terms of hundreds of milliseconds. So, it controls how the cell responds in a mid-term period of time, where you are actually capable of sensing it.
To this, a co-author of the Science paper, electrophysiologist Barry Brown, added, "One of the M-current's important properties is that it controls the membrane excitability to a large degree. So, it serves a unique role in that it acts as a brake on membrane depolarization."
Brown is a principal research scientist in diseases of the central nervous system, at DuPont Pharmaceuticals, in Wilmington, Del.
McKinnon and his co-authors cloned the genes that express the KCNQT2 and 3 proteins of the potassium channel. "It involved getting a good understanding of the native channel's biophysical properties, and how it works. Then we compared that to our cloned channels, and also their pharmacological properties. And that's where our collaboration with DuPont was quite important. It turns out they had developed a selective blocker of the M-current, which also is a selective blocker of these KCNQ2 and 3 channels."
DuPont's Brown told BioWorld Today: "We had characterized two compounds that were used in McKinnon's study, linopirdine and anthracenone, both potent and selective blockers of the M-current. We had done that in a variety of preparations, including hippocampal neurons. It was through the use of these compounds that David McKinnon was able to confirm that the combination of KCQT2 and 3 does in fact underlie the M-current. There are no other compounds available that inhibit M-current with the potency that these particular compounds display."
DuPont is clinically testing an analog of the anthracenone drug as a cognition-enhancing treatment for Alzheimer's disease (AD). "It's a very small trial," Brown observed, "primarily in Europe."
Alzheimer's, Yes; Epilepsy, Maybe
"Our oral drug candidate enhances the release of acetylcholine from the presynaptic terminal. The cholinergic neurons in the nucleus basalis that project to the hippocampus is one of the first areas to degenerate in AD."
But this AD drug, Brown pointed out, "wouldn't be used as a treatment for epilepsy, that's for sure, because it blocks the M-channel, which serves as a brake or damper on excitability. For an anti-epileptic, you would want to look for a drug that actually opened the M-channel, instead of blocking it."
McKinnon's university has applied to patent his potassium channels. "They would be good targets for drug development for anti-epileptics, if you could figure out how to activate them, and enhance their activity. That would damp down their neuronal excitability," he concluded. "It's not a wild-eyed idea." *