This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Colatsky, T. J. Search for Related Content PubMed PubMed Citation Articles by Colatsky, T. J.

(Circulation Research. 1996;78:1115-1116.)
© 1996 American Heart Association, Inc.

Articles

Antiarrhythmic Drug Binding Sites in Cardiac K⁺ Channels

Thomas J. Colatsky

From the Division of Cardiovascular and Metabolic Diseases, Wyeth-Ayerst Research, Princeton, NJ.

Correspondence to Thomas J. Colatsky, PhD, Division of Cardiovascular and Metabolic Diseases, Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543. E-mail colatst@war.wyeth.com.

Key Words: Editorials • quinidine • K⁺ channels • drug binding sites • drug-channel interactions • drug specificity

	Introduction

 
The picture that most of us carry in our minds of how drugs block ion channels is taken from the classic studies of Hille¹ involving local anesthetics and Armstrong² involving tetraethylammonium (TEA) derivatives. This picture is elegant in its simplicity yet robust enough to have provided a conceptual framework for explaining a variety of experimental results and for developing a rigorous model of the drug-channel interaction.^{3 4} We see cationic drugs entering the channel from the cytoplasmic side, only after the channel has opened, and binding to a site 20% to 50% of the way into the membrane field. Neutral drugs are not restricted to the open pore but can also access and leave the blocking site via a separate hydrophobic pathway. The movement of drugs into and out of the channel is ultimately governed by membrane potential and channel gating, producing use-dependent changes in membrane current and electrophysiological activity. Larger and more hydrophilic drugs move slowly and have slower use-dependent kinetics. Smaller and more hydrophobic drugs show rapid use dependence.

Molecular biology techniques have greatly refined this picture over the past several years by providing new and important structural detail. For K⁺ channels, TEA binding has been localized to a critical threonine residue in the P region of the channel that is highly conserved among different K⁺ channel subtypes.⁵ Specific amino acid residues in the predicted transmembrane S6 segment of domain IV (IVS6) were found to be critical determinants of local anesthetic action in Na⁺ channels^{6 7} and to govern the . . . [Full Text of this Article]