Mol Pharmacol 2020 06 2;97(6):355-364. Epub 2020 Apr 2.
Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands (M.Q., Y.J., M.J.C.H., F.R., D.F., W.B.H., M.A.G.H.); Department of Physiology, University of Kentucky, Lexington, Kentucky (T.D.G., B.P.D.); Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (W.B.H., A.S.-W.); Leiden Academic Centre for Drug Research, Division of Drug Discovery and Safety, Leiden, The Netherlands (A.P.I., L.H.H.); and Department of Medicine, University of Wisconsin, Madison, Wisconsin (C.T.J.)
Voltage-gated potassium 11.1 (K11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated K11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal K11.1 forward trafficking and thus reduce functional K11.1 channel densities. Although class III antiarrhythmics, e.g., dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use because of their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a K11.1 allosteric modulator/activator, to rescue K11.1 trafficking and produce functional K11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-K11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT K11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S-K11.1 cells, dofetilide (10 μM) or dofetilide + LUF7244 (10 + 5 μM) also restored K11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased I despite the presence of dofetilide (1 μM) in WT K11.1 cells. In G601S-expressing cells, long-term treatment (24-48 hour) with LUF7244 (10 μM) and dofetilide (1 μM) increased I compared with nontreated or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues K11.1 trafficking and produces functional I Thus, combined administration of LUF7244 and an I trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced K11.1 trafficking defects. SIGNIFICANCE STATEMENT: Decreased levels of functional K11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of K11.1 channel protein is an important factor in acquired and congenital long QT syndrome. LUF7244 as a negative allosteric modulator/activator in combination with dofetilide corrected both congenital and acquired K11.1 trafficking defects, resulting in functional K11.1 current.