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Yue Lab uncovers long-sought calcium channel interfaces targetable for therapy of cardiac and neurodegenerative diseases

April 16, 2013

Team members <em>(from left)</em> Hojjat Bazzazi; David T. Yue, M.D., Ph.D., Professor of Biomedical Engineering and Neuroscience, and Co-Director of the BME Ph.D. Program; Philemon Yang; and Manu Ben Johny

Team members (from left) Hojjat Bazzazi; David T. Yue, M.D., Ph.D., Professor of Biomedical Engineering and Neuroscience, and Co-Director of the BME Ph.D. Program; Philemon Yang; and Manu Ben Johny

JHU faculty member David T. Yue, M.D., Ph.D., Professor of Biomedical Engineering and Neuroscience and Co-Director of the BME Ph.D. Program and students Manu Ben Johny, Philemon Yang, and Hojjat Bazzazi, all of the Calcium Signals Laboratory, have published a landmark study in the journal Nature Communications.

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New view of CaM regulatory configurations of Ca CaV1.3 channels. > View larger image

The study entitled, “Dynamic switching of calmodulin interactions underlies Ca²+ regulation of CaV1.3 channels,” was published in the journal on April 16, 2013.This study culminates a decade long quest to identify the molecular states and the functional transitions that enable Ca²+-dependent inactivation of CaV channels, a vital form of autoregulation that tunes Ca²+ entry into cells. The authors developed a theoretical framework based on thermodynamic reasoning to relate the strength of an individual binding reaction within a complex network of states to its functional consequence. Then, by extensive mutagenesis of large channel segments, biochemical and functional characterization of these mutations, and theoretical insight, the authors identified dynamic movement of CaM on the channel as the mechanistic basis for Ca²+ regulation of CaV channel. The novel interfaces identified loom as promising therapeutic targets for both cardiac diseases such as arrhythmias and heart failure and neurodegenerative diseases including Parkinson's, Alzheimer's, and schizophrenia.

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