Careful study of genes responsible for rare Mendelian forms of human neurological disorders is an powerful approach for gaining insight into the causes, treatment, and potential cure for common, related diseases. The KCNQ genes were recently discovered as the result of the search for mutant genes causing Benign Neonatal Familial Convulsions, an autosomal dominant epileptic syndrome associated with seizures in infancy and throughout life. KCNQ genes encode voltage-dependent potassium channels called M-channels. M-channels regulate neuronal excitability by serving as effectors for neurotransmitter receptors and intracellular signaling pathways. Determining how these receptors and pathways modulate M-channels will enhance our ability to exploit M-channels as therapeutic targets in conditions involving excessive excitability or alterations and imbalances in modulatory neurotransmission, such as epilepsy, pain syndromes, and Alzheimer's disease. Because M-channels are large, oligomeric proteins and appear to be regulated by several distinct intracellular pathways, a novel, comprehensive approach to understanding their regulatory mechanisms is warranted. This proposed research approach exploits new instrumentation and analytical methods in mass spectrometry to identify sites of in vivo phosphorylation on KCNQ subunits. A combination of electrophysiological and cellular and molecular biological methods will then be used to determine the consequences of phosphorylation at the identified sites. The proposal involves a new collaboration between individuals with expertise in the clinical and genetic aspects of epilepsy, ion channel physiology, and proteomics. In addition to addressing specific questions concerning M-channel regulation, the proposed research will contribute to the development of mass spectrometric methods and the adaptation of these methods to the study of signaling proteins that are large, complex, and expressed either transiently, locally, or at low abundance in the brain. Because such signaling proteins play essential roles in brain development and in the maintenance of normal brain structure and activity, the proposed research may result in enhanced methodologies of broad usefulness for research into anomalous neurodevelopment, degeneration, and injury.
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