LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1

Muge Qile, Yuan Ji, Tyona D Golden, Marien J C Houtman, Fee Romunde, Doreth Fransen, Willem B van Ham, Ad P IJzerman, Craig T January, Laura H Heitman, Anna Stary-Weinzinger, Brian P Delisle, Marcel A G van der Heyden

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Voltage-gated potassium 11.1 (K v11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated K v11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal K v11.1 forward trafficking and thus reduce functional K v11.1 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 v11.1 allosteric modulator/activator, to rescue K v11.1 trafficking and produce functional K v11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-K v11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT K v11.1 levels was rescued by 10 mM dofetilide or 10 mM dofetilide + 5 mM LUF7244. In trafficking defective G601S-K v11.1 cells, dofetilide (10 mM) or dofetilide + LUF7244 (10 + 5 mM) also restored K v11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 mM) increased I Kv11.1 despite the presence of dofetilide (1 mM) in WT K v11.1 cells. In G601S-expressing cells, long-term treatment (24-48 hour) with LUF7244 (10 mM) and dofetilide (1 mM) increased I Kv11.1 compared with nontreated or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues K v11.1 trafficking and produces functional I Kv11.1. Thus, combined administration of LUF7244 and an I Kv11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced K v11.1 trafficking defects.

Original languageEnglish
Pages (from-to)355-364
Number of pages10
JournalMolecular Pharmacology
Volume97
Issue number6
DOIs
Publication statusPublished - Jun 2020

Fingerprint

Dive into the research topics of 'LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1'. Together they form a unique fingerprint.

Cite this