Structural studies of ion channel assembly and signaling

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DESCRIPTION (provided by applicant): The long-term goals of this project are to develop a high-resolution understanding of ion channel function and regulation. We are investigating the KCNQ family of voltage-gated potassium channels. These channels play central roles in auditory, cardiac, and brain function. Because channel function depends on subunit composition and interactions with proteins of cellular signaling networks, we are investigating the molecular bases for both of these phenomena. Due to difficulties in studying mammalian membrane protein structure, our present efforts are focused on understanding the function cytoplasmic domains that are important for channel assembly and for the recruitment of cellular signaling factors. We are pursuing a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect KCNQ channel function. Because of their important roles in human physiology, mutations of KCNQ channels lead to a variety of hereditary diseases including congenital deafness, cardiac arrhythmias, and epilepsy. We are particularly interested in understanding how disease mutations change channel properties and interactions with other proteins. KCNQ channels are the targets for drugs directed at cardiac arrhythmias, seizures, and memory disorders. Thus, understanding their structures and mechanisms of action may lead to the development of new, valuable therapeutic agents.