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. Voltage-dependent potassium channels (Kv) control the flow of K+ through the cell membrane in response to changes in membrane potential. The opening of Kv channels causes membrane hyperpolarization that can curtail excessive membrane excitability or simply tone down normal membrane activity. Kv channels are central to many fundamental biological processes, such as nerve conduction, muscle contraction, and hormone secretion.In a cell, Kv channels are always associated with many other proteins to form a macromolecular complex, and the associated proteins modulate channel functions. The long-term goal of our research is to develop an atomic level understanding of channel modulation mechanisms. In this project, we focus on modulation of Kv channel by beta subunit. We have found that beta subunit is an oxidoreductase that utilizes an NADPH cofactor to catalyze a redox reaction. We also found that beta subunit bound with an NADPH (reduced) or an NADP+ (oxidized) modulates channel function differently. We will solve high resolution structures of the beta subunit in complex with the whole potassium channel and with intracellular channel domains, in both reduced and in oxidized forms. We will also solve structures of the beta subunit in complex with small molecule modulators that affect channel functions.Acute changes in potassium current are observed in a variety of cells and are essential in initiating cellular responses to hypoxic conditions and oxidative stresses, but the mechanisms are often unknown. Beta subunit may play an important role in coupling intracellular redox chemistry to channel activities. Our study will address this possibility and lead to the elucidation of beta subunit???s physiological role in a cell.
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