Abstract

This Program Project is organized to study the structure-function and modulation of cardiac Na channels and their participation in excitation of the heart. It is a more focused continuation of a long-standing research program in cell biology of muscle. It will include a project devoted to Na channel gating and its unique cardiac properties, a project to study Na channel permeation and selectivity, a project to determine mechanisms of drug interaction with the Na channel, a core for molecular biology, and a core for computer/electronics/mechanical services. It will employ physiological, pharmacologica1, biophysical, and molecular biological tools to develop a better understanding of ion channel structure-function and to integrate these insights into a progressively improving molecular structural model of the channels. This insight is important to define channels as drug targets and as participants in the pathophysiology of cardiac arrhythmias.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL020592-22
Application #
2713966
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
1977-04-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
22
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Hilber, Karlheinz; Sandtner, Walter; Zarrabi, Touran et al. (2005) Selectivity filter residues contribute unequally to pore stabilization in voltage-gated sodium channels. Biochemistry 44:13874-82
Sandtner, Walter; Szendroedi, Julia; Zarrabi, Touran et al. (2004) Lidocaine: a foot in the door of the inner vestibule prevents ultra-slow inactivation of a voltage-gated sodium channel. Mol Pharmacol 66:648-57
Undrovinas, Albertas I; Maltsev, Victor A; Kyle, John W et al. (2002) Gating of the late Na+ channel in normal and failing human myocardium. J Mol Cell Cardiol 34:1477-89
Hilber, Karlheinz; Sandtner, Walter; Kudlacek, Oliver et al. (2002) Interaction between fast and ultra-slow inactivation in the voltage-gated sodium channel. Does the inactivation gate stabilize the channel structure? J Biol Chem 277:37105-15
Hilber, K; Sandtner, W; Kudlacek, O et al. (2001) The selectivity filter of the voltage-gated sodium channel is involved in channel activation. J Biol Chem 276:27831-9
Penzotti, J L; Lipkind, G; Fozzard, H A et al. (2001) Specific neosaxitoxin interactions with the Na+ channel outer vestibule determined by mutant cycle analysis. Biophys J 80:698-706
Sunami, A; Glaaser, I W; Fozzard, H A (2001) Structural and gating changes of the sodium channel induced by mutation of a residue in the upper third of IVS6, creating an external access path for local anesthetics. Mol Pharmacol 59:684-91
Martin, R L; Lee, J H; Cribbs, L L et al. (2000) Mibefradil block of cloned T-type calcium channels. J Pharmacol Exp Ther 295:302-8
Sunami, A; Glaaser, I W; Fozzard, H A (2000) A critical residue for isoform difference in tetrodotoxin affinity is a molecular determinant of the external access path for local anesthetics in the cardiac sodium channel. Proc Natl Acad Sci U S A 97:2326-31
Dudley Jr, S C; Chang, N; Hall, J et al. (2000) mu-conotoxin GIIIA interactions with the voltage-gated Na(+) channel predict a clockwise arrangement of the domains. J Gen Physiol 116:679-90

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