Abstract

The long term goal of this project is to gain an understanding of the molecular basis of cardiac excitability, concentrating on molecular structure-function relationships of cardiac K+ channels. The hypotheses to be tested are that specific regions and even specific amino acid residues are implicated in activation and deactivation gating and rectification of cardiac K channels.
The specific aims to be investigated include: (1) test of whether or not an extracellular ring of positive charges in hKv1.5 is a molecular determinant of outward rectification, (2) test whether or not the sixth transmembrane domain (S6) comprises part of the activation gate, This information should advance our understanding of the molecular physiology and pharmacology of cardiac K channels and further help in correlating cloned subunits with membrane currents in native cardiac cells. Finally, the information gained will expand our knowledge of the function of this important class of K channels, which may ultimately result in improved understanding of the genesis of cardiac arrhythmias and the development of better antiarrhythmic agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL047599-09
Application #
6330044
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Spooner, Peter
Project Start
1992-08-01
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2002-11-30
Support Year
9
Fiscal Year
2001
Total Cost
$174,382
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Yang, Zhenjiang; Shen, Wangzhen; Rottman, Jeffrey N et al. (2005) Rapid stimulation causes electrical remodeling in cultured atrial myocytes. J Mol Cell Cardiol 38:299-308
Williams, Christine P; Hu, NingNing; Shen, Wangzhen et al. (2002) Modulation of the human Kv1.5 channel by protein kinase C activation: role of the Kvbeta1.2 subunit. J Pharmacol Exp Ther 302:545-50
Zhou, J; Yi, J; Hu, N et al. (2000) Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes. Circ Res 87:33-8
Franqueza, L; Valenzuela, C; Eck, J et al. (1999) Functional expression of an inactivating potassium channel (Kv4.3) in a mammalian cell line. Cardiovasc Res 41:212-9
Rich, T C; Snyders, D J (1998) Evidence for multiple open and inactivated states of the hKv1.5 delayed rectifier. Biophys J 75:183-95
Uebele, V N; England, S K; Gallagher, D J et al. (1998) Distinct domains of the voltage-gated K+ channel Kv beta 1.3 beta-subunit affect voltage-dependent gating. Am J Physiol 274:C1485-95
Kupershmidt, S; Snyders, D J; Raes, A et al. (1998) A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current. J Biol Chem 273:27231-5
Yang, T; Snyders, D J; Roden, D M (1997) Inhibition of cardiac potassium currents by the vesnarinone analog OPC-18790: comparison with quinidine and dofetilide. J Pharmacol Exp Ther 280:1170-5
Yang, T; Snyders, D J; Roden, D M (1997) Rapid inactivation determines the rectification and [K+]o dependence of the rapid component of the delayed rectifier K+ current in cardiac cells. Circ Res 80:782-9
Yeola, S W; Snyders, D J (1997) Electrophysiological and pharmacological correspondence between Kv4.2 current and rat cardiac transient outward current. Cardiovasc Res 33:540-7

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