Experiments proposed are aimed at determining structural similarities of drug binding sites between channel types for mibefradil (the only highly specific agent for T-type Ca channels known at the present time) and phenylalkylamines, the drug class that competes with mibefradil, and for which some structural information is available for L-type calcium channels. Three channels will be used, the T-type Ca channel alpha lH, as a high affinity target for mibefradil and a somewhat lower affinity target of verapamil, the voltage-gated Na channel, a very low affinity target for mibefradil but a moderate affinity target for verapamil, and HERG, a high affinity target for both mibefradil and verapamil. In each area, experiments proposed combine site-directed mutagenesis, electrophysiology, and molecular modeling. In addition, experiments are proposed that will establish the channel specific or common effects on kinetics that control the action and efficacy of these agents as therapeutic drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065680-02
Application #
6390884
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Spooner, Peter
Project Start
2000-09-30
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$296,933
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
Bergson, Pamela; Lipkind, Gregory; Lee, Steven P et al. (2011) Verapamil block of T-type calcium channels. Mol Pharmacol 79:411-9
Lipkind, Gregory M; Fozzard, Harry A; Hanck, Dorothy A (2011) A molecular model of the inner pore of the Ca channel in its open state. Channels (Austin) 5:482-8
Edgerton, Gabrielle B; Blumenthal, Kenneth M; Hanck, Dorothy A (2010) Inhibition of the activation pathway of the T-type calcium channel Ca(V)3.1 by ProTxII. Toxicon 56:624-36
Bittner, Katie C; Hanck, Dorothy A (2008) The relationship between single-channel and whole-cell conductance in the T-type Ca2+ channel CaV3.1. Biophys J 95:931-41
Zhong, Xiaoli; Liu, Jinrong R; Kyle, John W et al. (2006) A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. Hum Mol Genet 15:1497-512
McNulty, Megan M; Kyle, John W; Lipkind, Gregory M et al. (2006) An inner pore residue (Asn406) in the Nav1.5 channel controls slow inactivation and enhances mibefradil block to T-type Ca2+ channel levels. Mol Pharmacol 70:1514-23
Freeze, Benjamin S; McNulty, Megan M; Hanck, Dorothy A (2006) State-dependent verapamil block of the cloned human Ca(v)3.1 T-type Ca(2+) channel. Mol Pharmacol 70:718-26
McNulty, Megan M; Hanck, Dorothy A (2004) State-dependent mibefradil block of Na+ channels. Mol Pharmacol 66:1652-61