LUF7244 plus Dofetilide Rescues Aberrant K v 11.1 Trafficking and Produces Functional I Kv11.1

• Published in: Molecular pharmacology 2020-06, Vol.97 (6), p.355-364
• Main Authors: Qile, Muge, Ji, Yuan, Golden, Tyona D, Houtman, Marien J C, Romunde, Fee, Fransen, Doreth, van Ham, Willem B, IJzerman, Ad P, January, Craig T, Heitman, Laura H, Stary-Weinzinger, Anna, Delisle, Brian P, van der Heyden, Marcel A G
• Format: Article
• Language: English
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.119.118190

Voltage-gated potassium 11.1 (K 11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated K 11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal K 11.1 forward trafficking and thus reduce functional K 11.1 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 K 11.1 allosteric modulator/activator, to rescue K 11.1 trafficking and produce functional K 11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-K 11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT K 11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S-K 11.1 cells, dofetilide (10 μM) or dofetilide + LUF7244 (10 + 5 μM) also restored K 11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased I despite the presence of dofetilide (1 μM) in WT K 11.1 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 K 11.1 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 K 11.1 trafficking defects. SIGNIFICANCE STATEMENT: Decreased levels of functional K 11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of K 11.1 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 K 11.1 trafficking defects, resulting in functional K 11.1 current.