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Robert S. Kass, Ph.D.
Chairman; Hosack Professor of Pharmacology; Alumni Professor of Pharmacology
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Research
Summary
Regulation of ion channel expression in normal and genetically-altered cardiac cells: gene-targeted pharmacology of inherited cardiac arrhythmias.
This laboratory focuses on understanding the fundamental mechanisms that underlie sudden cardiac death. A major effort in the laboratory is aimed at unraveling the structural and molecular changes that occur in heart ion channels in diseases caused by inherited mutations. These diseases include conduction abnormalities, dysfunction in synchrony of electrical signaling in the heart (Brugada Syndrome), and dysfunction in cardiac repolarization (the Long QT Syndrome). The approaches used are truly multi-disciplinary and involve collaborative efforts with clinical investigators studying and genotyping candidate patients with these disorders; the use of distinct and novel chemical probes of normal and dysfunctional ion channels; high resolution imaging techniques (see inset below) to determine the cellular localization of key ion channel proteins and signaling molecules in cardiac cells; the use of genetically-altered animals (mice) to study both the cellular and systems basis of these disorders; biophysical analysis of normal (wild type) and dysfunctional (mutant) ion channel activity using patch clamp procedures; biochemical analysis of protein-protein interactions that may be crucial in regulating electrical activity in cardiac cells; and computational approaches both in the analysis and prediction of protein structure and in the generation of "in silico" transgenic cells to predict how inherited mutations in ion channels might affect cellular function (dysfunction). We have focused on potassium and sodium channels that are expressed i the heart and are linked to cardiac arrhythimas, but we are beginning to explore similar mutation-induced ion channel dysfunction in the brain as applied to certain forms of inherited epilepsies and over seizure disorders. Our laboratory is fully equipped to carry out the electrophysiology, biochemical, imaging, and molecular biological procedures needed for this work.
http://www.cumc.columbia.edu/dept/cmt/participants/bios/kass.shtml
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Selected Publications:
1. Clancy, C. E., Kurokawa, J., Tateyama, M., Wehrens, X. H., & Kass, R. S. (2003a) K+ channel structure-activity relationships and mechanisms of drug- induced QT prolongation. Annu.Rev.Pharmacol.Toxicol.
43:441-461
2. Clancy, C. E., Tateyama, M., Liu, H., Wehrens, X. H., & Kass, R. S. (2003b) Non-Equilibrium Gating in Cardiac Na+ Channels: An Original Mechanism of Arrhythmia. Circulation
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3. Cormier, J. W., Rivolta, I., Tateyama, M., Yang, A. S., & Kass, R. S. (2002) Secondary Structure of the Human Cardiac Na+ Channel C Terminus. Evidence for a role of helical structures in modulation of channel inactivation. J.Biol.Chem.
277:9233-9241
4. Kurokawa, J., Chen, L., & Kass, R. S. (2003) Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc.Natl.Acad.Sci.U.S.A.
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5. Marx, S. O., Kurokawa, J., Reiken, S., Motoike, H., D'Armiento, J., Marks, A. R., & Kass, R. S. (2002) Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science
295:496-499
6. Splawski, I., Timothy, K. W., Tateyama, M., Clancy, C. E., Malhotra, A., Beggs, A. H., Cappuccio, F. P., Sagnella, G. A., Kass, R. S., & Keating, M. T. (2002) Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science
297:1333-1336
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