M-channels: neurological diseases, neuromodulation, and drug development

Abstract

Efforts in basic neuroscience and studies of rare hereditary neurological diseases are partly motivated by the hope that such work can lead to better understanding of and treatments for the common neurological disorders. An example is the progress that has resulted from identification of the genes that cause benign familial neonatal convulsions (BFNCs). Benign familial neonatal convulsions is a rare idiopathic, generalized epilepsy syndrome. In 1998, geneticists discovered that BFNC is caused by mutations in a novel potassium channel subunit, KCNQ2. Further work quickly revealed the sequences of 3 related brain channel genes KCNQ3, KCNQ4, and KCNQ5. Mutations in 2 of these genes were shown to cause BFNC (KCNQ3) and hereditary deafness (KCNQ4). Physiologists soon discovered that the KCNQ genes encoded subunits of the M-channel, a widely expressed potassium channel that mediates effects of modulatory neurotransmitters and controls repetitive neuronal discharges. Finally, pharmacologists discovered that the biological activities of 3 classes of compounds in development as treatments for Alzheimer disease, epilepsy, and stroke were mediated in part by effects on brain KCNQ channels. Cloned human KCNQ channels can now be used for high-throughput screening of additional drug candidates. Ongoing studies in humans and animal models will refine our understanding of KCNQ channel function and may reveal additional targets for therapeutic manipulation.