Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects

Abstract

Torsades de pointes (TdP) arrhythmia is a potentially fatal form of ventricular arrhythmia that occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings). A likely mechanism for QT interval prolongation and TdP arrhythmias is blockade of the rapid component of the cardiac delayed rectifier K⁺ current (I_Kr), which is encoded by human ether-a-go-go-related gene (HERG). Over 100 non-cardiovascular drugs have the potential to induce QT interval prolongations in the electrocardiogram (ECG) or TdP arrhythmias. The binding site of most HERG channel blockers is located inside the central cavity of the channel. An evaluation of possible effects on HERG channels during the development of novel drugs is recommended by international guidelines. During cardiac ischaemia activation of ATP-sensitive K⁺ (K_ATP) channels contributes to action potential (AP) shortening which is either cardiotoxic by inducing re-entrant ventricular arrhythmias or cardioprotective by inducing energy-sparing effects or ischaemic preconditioning (IPC). K_ATP channels are formed by an inward-rectifier K⁺ channel (Kir6.0) and a sulfonylurea receptor (SUR) subunit: Kir6.2 and SUR2A in cardiac myocytes, Kir6.2 and SUR1 in pancreatic β-cells. Sulfonylureas and glinides stimulate insulin secretion via blockade of the pancreatic β-cell K_ATP channel. Clinical studies about cardiotoxic effects of sulfonylureas are contradictory. Sulfonylureas and glinides differ in their selectivity for pancreatic over cardiovascular K_ATP channels, being either selective (tolbutamide, glibenclamide) or non-selective (repaglinide). The possibility exists that non-selective K_ATP channel inhibitors might have cardiovascular side effects. Blockers of the pore-forming Kir6.2 subunit are insulin secretagogues and might have cardioprotective or cardiotoxic effects during cardiac ischaemia.

Introduction

Ion channels are membrane-spanning protein complexes that allow ions to travel across the lipid bilayer and take part in fundamental cellular processes of almost all organisms. K⁺ channels are a large family that show K⁺ ion selectivity and play a central role in the electrical activity of excitable cells. Since cloning and identification of the first K⁺ channel gene (Shaker) from Drosophila in 1987 (Papazian et al., 1987), more than 80 genes encoding human K⁺ channels have been cloned. Three main classes of K⁺ channels can be identified on the basis of the transmembrane topology of the pore-forming α-subunits: (1) 6 transmembrane helix (6TM) voltage-gated K⁺ channels (Kv), which are activated by membrane depolarization; (2) 2 transmembrane helix (2TM) inward rectifier K⁺ channels (Kir), which are activated by intracellular factors such as G-proteins, nucleotides or polyamines; (3) 4 transmembrane helix (4TM) 2-pore K⁺ channels. In the case of both Kv and Kir channels, the K⁺ channel has a tetrameric structure formed by the assembly of 4 α-subunits (reviews in Tamargo et al., 2004, Recanatini et al., 2005). Co-expression of K⁺ channel β-subunits with α-subunits regulates cell surface expression, gating kinetics and drug-sensitivity of K⁺ channels. K⁺ channel β-subunits represent a diverse molecular group, which includes cytoplasmic proteins (Kvβ1–3, K⁺ channel-interacting proteins (KChIP) and K⁺ channel-associated proteins (KChAP)) which interact with the intracellular domains of Kv channels, single transmembrane spanning domains, such as minK and minK-related proteins (MiRP) encoded by the KCNE gene family, and ATP-binding cassette (ABC) transport-related proteins, such as the sulfonylurea receptor (SUR) for the inward rectifiers Kir6.0 (review in Pourrier et al., 2003). With regard to the structural characteristics of the pore-forming region of the K⁺ channels, several evidences have been provided by crystallographic studies carried out on bacterial K⁺ channels first by the recent Nobel Laureate R. MacKinnon (Doyle et al., 1998).

Action potentials (AP) of the cardiac ventricular myocyte can last for several hundred milliseconds (about 200–400 ms; Fig. 1). This prolonged depolarization (plateau) phase is essential for normal excitation-contraction coupling and renders the cell relatively refractory to premature excitation. Cardiac APs are long because the many types of K⁺ channels that repolarize the membrane either activate slowly, inactivate rapidly, or conduct less current at positive membrane potentials. The principal K⁺ currents participating in the repolarization of the AP in ventricular myocytes are (Fig. 1 top left): a transient outward K⁺ current (I_to), the delayed rectifier K⁺ current (I_K) and the inward rectifier K⁺ current (I_K1). Each of these currents has relatively different importance at different stages of the AP. I_to contributes to the initial repolarization phase of the AP—the “notch”. I_K is the major time-dependent outward current that participates in mediating repolarization of the cardiac AP and, therefore, plays an important role in determining the duration of the AP (Noble & Tsien, 1969). The delayed rectifier K⁺ current I_K in ventricular myocytes consists of a rapid component (cardiac rapidly activating delayed rectifier K⁺ current, I_Kr) and a slow component (cardiac slowly activating delayed rectifier K⁺ current, I_Ks). These 2 components have first been described by Sanguinetti and Jurkiewicz (1990) and have also been detected in human ventricular cells (Li et al., 1996). I_K1 determines the resting membrane potential and also contributes to the terminal repolarization phase. During ischaemia, the ATP-sensitive K⁺ (K_ATP) current (I_KATP) becomes important and contributes to AP shortening in ischaemic myocardium (reviews in Rees & Curtis, 1996, Sanguinetti & Keating, 1997).

This review describes the main repolarizing K⁺ channels in the heart under physiological conditions (I_Kr/human ether-a-go-go-related gene (HERG) channels) and under ischaemic conditions (K_ATP channels) as targets for cardiotoxic effects of drugs which act as inhibitors of the open probabilities of these channels. Furthermore, this review also describes the pore-forming Kir6.2 subunit of the K_ATP channel as a target for both cardiac and hypoglycemic effects of drugs, since K_ATP channels also play a major role in the regulation of insulin secretion from pancreatic β-cells and pancreatic β-cells express the same pore-forming Kir6.2 subunit of the K_ATP channel as cardiac myocytes. HERG and K_ATP channels serve as examples for drug targets involved in mechanisms underlying cardiotoxic effects and (in case of K_ATP channels) also in mechanisms leading to alterations of blood glucose homeostasis.