Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology

Abstract

Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity.

Keywords: Gating; KCNA5; KCNE1; KCNQ1; Pharmacology; Potassium channel; hERG.

Fig. 1

Structural features of voltage-gated K⁺ channels. A, Functional channels are composed of four identical or highly related α-subunits. The S1–S4 transmembrane segments form the VSD. The S5 and S6 segments form the pore domain. In I_Ks channels, four KCNQ1 α-subunits are joined by two (or more) KCNE1 β-subunits that are positioned in the cleft as indicated. From Nakajo K. and Kubo Y. KCNQ1 channel modulation by KCNE proteins via the voltage-sensing domain. J Physiol. 2015;593:2617–2625. B, side-view of the pore domain of the KcsA bacterial K⁺ channel in a closed state. Only two of the four subunits are shown; selectivity filter is boxed. c, the selectivity filter of a K⁺ channel (KcsA) is a narrow lumen where dehydrated K⁺ ions (green sphere) transiently bind to sites (1–4) formed by oxygen atoms contributed by TYGYG residues that form the structure. Bottom panel shows a single K⁺ ion surrounded by 8 water molecules. B and C: From Alam A. and Youxing J. Structural studies of ion selectivity in tetrameric cation channels. J Gen Physiol. 2011;137(5):397–403; with permission.

Fig. 2

K⁺ channel inhibitors. A, Model of the hERG1 channel pore domain showing block of the central cavity by MK-499, a class III antiarrhythmic agent. The S5 and S6 segments for two of the four subunits are shown. The key binding residues in the S6 segment (Y652 and F656) are indicated. From Mitcheson JS, Chen J, Lin M, Culberson C, and Sanguinetti MC A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA. 2000;97:12329–12333. B and C, Psora-4 (orange) binds to multiple sites on the Kv1.5 channel viewed from the extracellular space (B) or from the side (C). From Marzian S, Stansfeld PJ, Rapedius M, et al. Side pockets provide the basis for a new mechanism of Kv channel-specific inhibition. Nat Chem Biol. 2013;9:507–513; with permission.

Fig. 3

Binding site for ICA-105574, a hERG1 channel activator. A, open-state pore domain of the channel as viewed from the extracellular space. ICA is shown in space fill occupying one of the four symmetrical sites available. VSDs are not shown. B, side view of the binding site with important binding sites residues indicated in single letter code. From Garg V, Stary-Weinzinger A, Sachse F, Sanguinetti, MC. Molecular determinants for activation of human ether-a-go-go-related gene 1 potassium channels by 3-nitro-n-(4-phenoxyphenyl) benzamide. Mol Pharmacol. 2011;80:630–637; with permission.