Molecular Determinants of hERG Channel Block by Terfenadine and Cisapride

Abstract

Abstract. Block of cardiac hERG K + channels by the antihistamine terfenadine and the prokinetic agent cisapride is associated with prolonged ventricular repolarization and an increased risk of ventricular arrhythmia. Here, we used a site-directed mutagenesis approach to determine the molecular determinants of hERG block by terfenadine and cisapride. Wild-type and mutant hERG channels were heterologously expressed in Xenopus laevis oocytes and characterized by measuring whole cell currents with two-microelectrode voltage clamp techniques. Mutation of T623, S624, Y652, or F656 to Ala reduced channel sensitivity to block by terfenadine. The same mutations reduced sensitivity to cisapride. These data confirm our previous findings that polar residues (T623, S624) located near the base of the pore helix and aromatic residues (Y652, F656) located in the S6 domain are key molecular determinants of the hERG drug binding site. Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. As previously proposed by molecular modeling studies (Farid R, et al. Bioorg Med Chem. 2006;14:3160-3173), our findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG.

Temperature Effects on Kinetics of KV11.1 Drug Block Have Important Consequences for In Silico Proarrhythmic Risk Prediction

“…This access may be made less tortuous as a result of increased thermal motion as temperature is increased, thus accelerating the rate of the diffusion step. Alternately, as the drug is thought to enter the channel via the cytoplasmic end of the channel pore (Kamiya et al, 2008), it must diffuse through the lipid membrane after application to the extracellular solution. Since the lipid membrane has been shown to become more fluidic with increasing temperatures (Carratu et al, 1996;Vigh et al, 1998), this potentially allows the drug to diffuse more easily at higher temperatures (Gaede and Gawrisch, 2003).…”

Mechanism of hERG Channel Block by the Psychoactive Indole Alkaloid Ibogaine

“…The putative binding pocket comprises several amino acids within the pore helix of the S6 domain, among which two aromatic residues, Tyr652 and Phe656, are of utmost importance (Perry et al, 2010). Mutation of these aromatic residues to, for example, alanine, greatly reduces the potencies of several hERG channel blockers including cisapride, halofantrine, quinidine, ketoconazole, and MK-499 (Mitcheson et al, 2000;Sánchez-Chapula et al, 2002Ridley et al, 2006;Kamiya et al, 2008). Likewise, the IC 50 of ibogaine for current inhibition was significantly reduced in these mutants (Fig.…”

Kinetics of Drug Interaction with the Kv11.1 Potassium Channel

“…It is well established that drug block of K v 11.1 can be voltage- (Paul et al, 2002;Witchel et al, 2004;Kamiya et al, 2008) and state-dependent (Perrin et al, 2008), and these properties may vary substantially from drug to drug (Perrin et al, 2008). Consequently, the apparent IC 50 can vary considerably depending on the voltage protocol used to measure block (Kirsch et al, 2004;Milnes et al, 2010).…”