ICa(TTX) is a sodium current component seen in a number of neural and cardiac preparations. In each case, ICa(TTX) channels were found to express both different gating and different permeability properties from the main body of sodium current in that cell type. For rat ventricular cells we have shown that ICa(TTX) channels are encoded by a different gene from that encoding the classical cardiac sodium current. As expected from the very existence of a clear current component, ICa(TTX) channels do affect the electrical behavior of ventricular cells and can even generate action potentials. ICa(TTX) activates over a more negative range of potentials than the classical cardiac sodium current. It should, then, act to amplify the depolarization delivered to a ventricular cell and so provide the immediate trigger for the cardiac action potential. Owing to this role, ICa(TTX) could be of considerable importance in cardiac arrhythmias and in their control. It has been reported in both human atrial and ventricular cells. We have, then, a new channel encoded by a distinct gene that contributes to cardiac cell electrical behavior. The potential importance of this channel for both normal and pathological cardiac electrophysiology calls for its extensive study. We propose to: (i) Determine the slow inactivation properties of ICa(TTX) and compare them to those of the classical sodium current. The slow inactivation process is critical for determining the stationary state pool of available sodium channels. The expected role of ICa(TTX) as the immediate trigger for the cardiac action potential suggests that its slow inactivation properties (and defects in them) could have disproportionately strong effects on the generation and conduction of the cardiac action potentials. (ii) Quantitatively determine the selectivity sequence of ICa(TTX) channels to both mono- and divalent ions. The characteristics of a current component are determined by it selectivity as well as its gating properties. This will be the first determination of the alkali ion selectivity of a native sodium channel that expresses high calcium permeability and could be of importance for the emerging picture of the structural basis for ion selectivity in typical sodium channels. (iii) Start the molecular identification of ICa(TTX) channels by use of antisense oligonucleotides directed against the several sodium channel isoforms known to be expressed in cardiac cells. (iv) Compare the properties of ICa(TTX) in normal and failing human hearts to see if alterations in its properties correlate with pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068733-02
Application #
6795076
Study Section
Special Emphasis Panel (ZRG1-HEM-2 (02))
Program Officer
Lathrop, David A
Project Start
2003-09-01
Project End
2005-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$371,250
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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