The central role of Na channels in excitable cells gives it a critical role in normal and abnormal behavior. Its gating is a complex system, and even modest dysfunction of gating results in debilitating disease or death. The long term goal of this proposal is to understand the structure and function of the cardiac Na channel as a key contributor to normal and abnormal excitation and conduction and as a target of drugs to treat arrhythmias. For the first time sufficient information is available that we can hope to connect the action of drugs to limit permeation with their action to affect gating. The goals of the proposal for the next five years are to 1) Identify the conformational changes of S6 segments during activation; 2) Identify conformational changes in S6 during fast inactivation and their relation to S4 movements; 3) Determine the molecular features of local anesthetic drug binding and the mechanism of action; and 4} Locate superficial residues on S6 and S5 helices in relation to S4 segments. The experiments proposed combine molecular techniques with electrophysiology, principally whole cell ionic and gating current recordings, and molecular modeling to identify conformational changes in the inner pore S5 and S6 segments in response to S4 voltage sensor movement and drug binding. A key element of the proposal is to integrate: experimental data, both our own and that of others, into a molecular model of the relationship between ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065661-07
Application #
7210743
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2000-09-29
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$361,494
Indirect Cost
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Lipkind, Gregory M; Fozzard, Harry A (2010) Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore. Mol Pharmacol 78:631-8
Hanck, Dorothy A; Nikitina, Elena; McNulty, Megan M et al. (2009) Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity. Circ Res 105:492-9
Maltsev, Victor A; Kyle, John W; Undrovinas, Albertas (2009) Late Na+ current produced by human cardiac Na+ channel isoform Nav1.5 is modulated by its beta1 subunit. J Physiol Sci 59:217-25
Edgerton, Gabrielle B; Blumenthal, Kenneth M; Hanck, Dorothy A (2008) Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5. Toxicon 52:489-500
Maltsev, Victor A; Kyle, John W; Mishra, Sudhish et al. (2008) Molecular identity of the late sodium current in adult dog cardiomyocytes identified by Nav1.5 antisense inhibition. Am J Physiol Heart Circ Physiol 295:H667-76
Fozzard, Harry A (2008) Increased sensitivity to local anesthetic drugs: bedside to bench. Circ Res 103:325-7
Hanck, Dorothy A; Sheets, Michael F (2007) Site-3 toxins and cardiac sodium channels. Toxicon 49:181-93
McNulty, Megan M; Edgerton, Gabrielle B; Shah, Ravi D et al. (2007) Charge at the lidocaine binding site residue Phe-1759 affects permeation in human cardiac voltage-gated sodium channels. J Physiol 581:741-55
Jane-wit, Daniel; Altuntas, Cengiz Z; Johnson, Justin M et al. (2007) Beta 1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis. Circulation 116:399-410
Khan, A; Kyle, J W; Hanck, D A et al. (2006) Isoform-dependent interaction of voltage-gated sodium channels with protons. J Physiol 576:493-501

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