Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

MOLECULAR DETERMINANTS OF DRUG BINDING AND ACTION ON L-TYPE CALCIUM CHANNELS

MOLECULAR DETERMINANTS OF DRUG BINDING AND ACTION ON L-TYPE CALCIUM CHANNELS ▪ Abstract The crucial role of L-type Ca 2+ channels in the initiation of cardiac and smooth muscle contraction has made them major therapeutic targets for the treatment of cardiovascular disease. L-type channels share a common pharmacological profile, including high-affinity voltage- and frequency-dependent block by the phenylalkylamines, the benz(othi)azepines, and the dihydropyridines. These drugs are thought to bind to three separate receptor sites on L-type Ca 2+ channels that are allosterically linked. Results from different experimental approaches implicate the IIIS5, IIIS6, and IVS6 transmembrane segments of the α 1 subunits of L-type Ca 2+ channels in binding of all three classes of drugs. Site-directed mutagenesis has identified single amino acid residues within the IIIS5, IIIS6, and IVS6 transmembrane segments that are required for high-affinity binding of phenylalkylamines and/or dihydropyridines, providing further support for identification of these transmembrane segments as critical elements of the receptor sites for these two classes of drugs. The close proximity of the receptor sites for phenylalkylamines, benz(othi)azepines, and dihydropyridines raises the possibility that individual amino acid residues may be required for high-affinity binding of more than one of these ligands. Therefore, we suggest that phenylalkylamines and dihydropyridines bind to different faces of the IIIS6 and IVS6 transmembrane segments and, in some cases, bind to opposite sides of the side chains of the same amino acid residues. The results support the domain interface model for binding and channel modulation by these three classes of drugs. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annual Review of Pharmacology and Toxicology Annual Reviews

MOLECULAR DETERMINANTS OF DRUG BINDING AND ACTION ON L-TYPE CALCIUM CHANNELS

Loading next page...
 
/lp/annual-reviews/molecular-determinants-of-drug-binding-and-action-on-l-type-calcium-usqpPX08sE

References (120)

Publisher
Annual Reviews
Copyright
Copyright © 1997 by Annual Reviews Inc. All rights reserved
Subject
Review Articles
ISSN
0362-1642
eISSN
1545-4304
DOI
10.1146/annurev.pharmtox.37.1.361
pmid
9131258
Publisher site
See Article on Publisher Site

Abstract

▪ Abstract The crucial role of L-type Ca 2+ channels in the initiation of cardiac and smooth muscle contraction has made them major therapeutic targets for the treatment of cardiovascular disease. L-type channels share a common pharmacological profile, including high-affinity voltage- and frequency-dependent block by the phenylalkylamines, the benz(othi)azepines, and the dihydropyridines. These drugs are thought to bind to three separate receptor sites on L-type Ca 2+ channels that are allosterically linked. Results from different experimental approaches implicate the IIIS5, IIIS6, and IVS6 transmembrane segments of the α 1 subunits of L-type Ca 2+ channels in binding of all three classes of drugs. Site-directed mutagenesis has identified single amino acid residues within the IIIS5, IIIS6, and IVS6 transmembrane segments that are required for high-affinity binding of phenylalkylamines and/or dihydropyridines, providing further support for identification of these transmembrane segments as critical elements of the receptor sites for these two classes of drugs. The close proximity of the receptor sites for phenylalkylamines, benz(othi)azepines, and dihydropyridines raises the possibility that individual amino acid residues may be required for high-affinity binding of more than one of these ligands. Therefore, we suggest that phenylalkylamines and dihydropyridines bind to different faces of the IIIS6 and IVS6 transmembrane segments and, in some cases, bind to opposite sides of the side chains of the same amino acid residues. The results support the domain interface model for binding and channel modulation by these three classes of drugs.

Journal

Annual Review of Pharmacology and ToxicologyAnnual Reviews

Published: Apr 1, 1997

There are no references for this article.