description): T-type Ca channels are present in a wide variety of cell types (cardiac myocytes, smooth muscle cells and neurons), and participate in various physiological functions such as pacemaking in heart and shaping bursting behavior in neurons. Their expression is upregulated under certain pathological conditions such as myocardial hypertrophy. This suggests that the T-type Ca channels may be involved in the progression of disease processes, or may be a valuable target of therapies. Recently, several isoforms of T-type channel pore-forming subunits have been cloned (alpha-1G, -1H, and -1I), providing an opportunity to study the molecular structure, physiology and pharmacology of this class of channels. In this proposal, the applicant proposes to investigate the structural basis of gating and ion selectivity/permeation of T-type Ca channels.
Five specific aims are proposed to test two general hypotheses: (1) the steep voltage-dependence of inactivation from closed states of T-type Ca channels arises from activation gating, and (2) differences in selectivity between low- and high-voltage activated Ca channels and between Ca and Na channels arise from a focal set of differences in pore residues between these channel families. These experiments will use techniques of electrophysiology, mutagenesis and molecular modeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062603-02
Application #
6390365
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Spooner, Peter
Project Start
2000-09-20
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$297,104
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637