Potassium channels: how genetic studies of epileptic syndromes open paths to new therapeutic targets and drugs.
How can epilepsy gene hunting lead to better care for patients with epilepsy? Lessons may be learned from the progress made by identifying the mutated genes that cause Benign Familial Neonatal Convulsions (BFNC). In 1998, a decade of clinical and laboratory-based genetics work resulted in the cloning of the KCNQ2 potassium channel gene at the BFNC locus on chromosome 20. Subsequently, computer "mining" of public DNA databases allowed the rapid identification of three more brain KCNQ genes. Mutations in each of these additional genes were implicated as causes of human hereditary diseases: epilepsy (KCNQ3), deafness (KCNQ4), and, possibly, retinal degeneration (KCNQ5). Physiologists discovered that the KCNQ genes encoded subunits of the "M-channel," a type of potassium channel known to control repetitive neuronal discharges. Finally, pharmacologists discovered that retigabine, a novel anticonvulsant with a broad but distinctive efficacy profile in animal studies, was a potent KCNQ channel opener. These studies suggest that KCNQ channels may be an important new class of targets for anticonvulsant therapies. The efficacy of retigabine is currently being tested in multicenter clinical trials; identification of its molecular targets will allow it to be more efficiently exploited as a "lead compound." Cloned human KCNQ channels can now be expressed in cultured cells for "high-throughput" screening of drug candidates. Ongoing studies of the KCNQ channels in humans and animal models will refine our understanding of how M-channels control excitability at the cellular, network, and behavioral levels, and may reveal additional targets for therapeutic manipulation.
Cooper
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Department of Neurology, Northern California Comprehensive Epilepsy Center, University of California, San Francisco 94143-0725, USA. ecooper@itsa.ucsf.edu
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002219:Carbamates / Q000494:pharmacology; D002986:Clinical Trials as Topic; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D020936:Epilepsy, Benign Neonatal / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000502:physiology; D010655:Phenylenediamines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011976:Receptors, Muscarinic; C101866:ezogabine