Calcium channel block by (-)devapamil is affected by the sequence environment and composition of the phenylalkylamine receptor site
| Autor: | Stefan Aczél, Frank Döring, Jörg Mitterdorfer, Degtiar' Ve, Steffen Hering, D. Kimball, Stanislav Berjukow, Eugen Timin |
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| Rok vydání: | 1997 |
| Předmět: |
Devapamil
Calcium Channels L-Type Macromolecular Substances Recombinant Fusion Proteins Xenopus Biophysics N-type calcium channel Membrane Potentials chemistry.chemical_compound Animals Channel blocker Binding site Sequence Deletion Binding Sites Voltage-dependent calcium channel Calcium channel biochemical phenomena metabolism and nutrition Calcium Channel Blockers Molecular biology R-type calcium channel Transmembrane domain chemistry Verapamil Mutagenesis Site-Directed Oocytes Calcium Channels Research Article |
| Zdroj: | Biophysical Journal. 73(1):157-167 |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/s0006-3495(97)78056-1 |
| Popis: | The pore-forming alpha 1 subunit of L-type calcium (Ca2+) channels is the molecular target of Ca2+ channel blockers such as phenylalkylamines (PAAs). Association and dissociation rates of (-)devapamil were compared for a highly PAA-sensitive L-type Ca2+ channel chimera (Lh) and various class A Ca2+ channel mutants. These mutants carry the high-affinity determinants of the PAA receptor site in a class A sequence environment. Apparent drug association and dissociation rate constants were significantly affected by the sequence environment (class A or L-type) of the PAA receptor site. Single point mutations affecting the high-affinity determinants in segments IVS6 of the PAA receptor site, introduced into a class A environment, reduced the apparent drug association rates. Mutation I1811M in transmembrane segment IVS6 (mutant AL25/-I) had the highest impact and decreased the apparent association rate for (-)devapamil by approximately 30-fold, suggesting that this pore-lining isoleucine in transmembrane segment IVS6 plays a key role in the formation of the PAA receptor site. In contrast, apparent drug dissociation rates of Ca2+ channels in the resting state were almost unaffected by point mutations of the PAA receptor site. |
| Databáze: | OpenAIRE |
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