This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Potassium channels and chloride channels contribute to many important physiological processes including the production of electrical signals, osmotic control, and signaling the release of hormones and transmitters. They are targets of numerous pharmacological agents, and mutations of these channel genes have been associated with a variety of debilitating diseases. The structural study of ion channels is a relatively new research field. We have solved the structures of three potassium channels (KcsA, the ligand gated MthK channel, and the recently published voltage gated KvAP channel) and of one chloride channel (ClC-class). These structures begin to reveal the fundamental principles of ion conduction and channel gating (the regulated opening and closing of the channel). Our current work focuses on mechanisms by which ion channels gate. The structure of the MthK channel revealed for the first time the structural mechanisms of ligand gating in potassium channels. Projects on the structure solution of cytoplasmic domains of inward rectifier potassium channels and of the Ca activated potassium channels in their liganded and unliganded form aim to gain deeper insight into the mechanisms of gating in different ligand gated potassium channels. Another large ongoing project concerns the structural basis of voltage dependent gating in potassium channels. The structure of the KvAP channel provided the first glimpse into how voltage dependent gating in Potassium channels works. We are continuing to investigate the mechanism of voltage gating by solving the structure of the channel in different conformations. Gating in ClC channels is very different from potassium channels.
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