Abstract

The long term goals are to obtain as complete a description as possible of the electrophysiological behavior of four channels in the cardiac sarcolemmma (SL). These are the Na, Ca, inwardly rectifying K (IRK) and transient K (TK) channels. For Na channels, particular emphasis will be placed upon the slow component of inactivation and its significance in the interpretation of single channel results. In addition the effects of antiarrhythmic agents and ischemia (specifically pH changes) upon Na channel behavior, will be examined. For Ca channels, features specific for cardiac function will be studied. How do cardiac Ca channel agonists work, how does norepinephrine increase Ca currents, and how is cardiac SL Ca current linked to cardiac SR Ca release? For IRK, I am interested in both the effects of ionic blockers including K ion, on opening probability, and on channel selectivity. Two possible regulatory components of TK, potential and Cai will be studied and the possible relationship between TK and IRK investigated. Single channels will be isolated using the patch gigaseal method and appropriately selected solutions. The usual patch configurations will be employed. Currents from larger numbers of channels will be studied using outside-out patches, or whole cell currents. For the latter, a single electrode voltage clamp method in which potential is measured directly will be used, although the I-V converter patch clamp method may be used as well. In both cases the patch pipette will be perfused. Impedance and noise measurements will also be done. A combined approach is necessary because single channel studies are bandwidth-limited due to low signal-to-noise for Ca and Na channels particularly. Computer programs have been developed to automate data analysis. In addition models of channel behavior can be analyzed. These are sequential schemes in which transitions between states form a Markov chain. Identifiability methods are used to determine the data sets necessary for evaluating a particular model.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036930-04
Application #
3352307
Study Section
Physiology Study Section (PHY)
Project Start
1985-12-01
Project End
1990-06-30
Budget Start
1988-12-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

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
Brown, Arthur M (2005) HERG block, QT liability and sudden cardiac death. Novartis Found Symp 266:118-31; discussion 131-5, 155-8
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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