The long-term goal is to understand bow voltage-dependent ion channels produce the human cardiac action potential.
The specific aims are to: 1) fully characterize three different inward rectifier K+ channels (IRKs) that we have identified in human heart (hhIRKs); 2) characterize an accessory subunit which may be associated with hhIRKs; 3) examine the effects of Class III antiarrhythmic drugs (AADs) on the newly identified hhIRKs; 4) determine whether naturally occurring, cytoplasmic polyamines are physiological blockers of hhlRKs; and 5) examine mechanisms of action of Class III AADs on voltage-dependent outward rectifier K+ channels (ORKs) cloned from human heart and interactions among ORKs, Class III AADs and a novel human heart ORK beta-subunit. The broad hypothesis being tested is that mechanistic studies of the effects of antiarrhythmic drugs can be performed directly on human cardiac ion channels rather than inferred from studies on non-human animals. The health relatedness of the project derives from two facts: cardiac arrhythmias are the main cause of death in the USA, and satisfactory antiarrhythmic therapy remains to be achieved. This research, therefore, sits at the interface between basic and clinical studies of cardiac electrophysiology. The research is focussed on K+ channels which are the primary targets for Class III antiarrhythmic drugs. In particular, new information is being accumulated concerning the complexity of the inward rectifier K + current IK1 which sets the resting potential of cardiomyocytes and is important for terminal repolarization of the cardiac action potential. The research design uses recombinant DNA methods to clone IRKs and ORKs from human heart tissue, to express the cloned channels stably or transiently in heterologous cells and to mutagenize the channels for aid in understanding the mechanistic actions of cardiac antiarrhythmic drugs. Electrophysiological methods are used to study the expressed ion channels and to compare their functional properties in heterologous cells to their properties when they are expressed in their native human cardiomyocyte environment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036930-15
Application #
6043745
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-12-01
Project End
2000-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Physiology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kuryshev, Yuri A; Ficker, Eckhard; Wang, Lu et al. (2005) Pentamidine-induced long QT syndrome and block of hERG trafficking. J Pharmacol Exp Ther 312:316-23
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Brown, A M (2004) Drugs, hERG and sudden death. Cell Calcium 35:543-7
Ficker, Eckhard; Kuryshev, Yuri A; Dennis, Adrienne T et al. (2004) Mechanisms of arsenic-induced prolongation of cardiac repolarization. Mol Pharmacol 66:33-44
Ficker, Eckhard; Dennis, Adrienne T; Wang, Lu et al. (2003) Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG. Circ Res 92:e87-100
Obejero-Paz, Carlos A; Yang, Tianen; Dong, Wei-Qiang et al. (2003) Deferoxamine promotes survival and prevents electrocardiographic abnormalities in the gerbil model of iron-overload cardiomyopathy. J Lab Clin Med 141:121-30
Laurita, Kenneth R; Chuck, Emil Thomas; Yang, Tianen et al. (2003) Optical mapping reveals conduction slowing and impulse block in iron-overload cardiomyopathy. J Lab Clin Med 142:83-9
Schwalbe, Ruth A; Rudin, Alicia; Xia, Shen-Ling et al. (2002) Site-directed glycosylation tagging of functional Kir2.1 reveals that the putative pore-forming segment is extracellular. J Biol Chem 277:24382-9
Ficker, Eckhard; Obejero-Paz, Carlos A; Zhao, Shuxia et al. (2002) The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem 277:4989-98
Wible, Barbara A; Wang, Liming; Kuryshev, Yuri A et al. (2002) Increased K+ efflux and apoptosis induced by the potassium channel modulatory protein KChAP/PIAS3beta in prostate cancer cells. J Biol Chem 277:17852-62

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