RT Journal Article
SR Electronic
T1 LUF7244 plus dofetilide rescues aberrant Kv11.1 trafficking and produces functional IKv11.1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.119.118190
DO 10.1124/mol.119.118190
A1 M. Qile
A1 Y. Ji
A1 T.D. Golden
A1 M.J.C. Houtman
A1 F. Romunde
A1 D. Fransen
A1 W.B. van Ham
A1 A.P. IJzerman
A1 C.T. January
A1 L.H. Heitman
A1 A. Stary-Weinzinger
A1 B.P. Delisle
A1 M.A.G. van der Heyden
YR 2020
UL http://molpharm.aspetjournals.org/content/early/2020/04/02/mol.119.118190.abstract
AB Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g. dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use due to their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue WT or G601S Kv11.1 trafficking as shown by western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S Kv11.1 cells, dofetilide (10 μM) or dofetilide+LUF7244 (10+5 μM) restored Kv11.1 trafficking also, as demonstrated by western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased IKv11.1 despite the presence of dofetilide (1 μM) in WT Kv11.1 cells. In G601S expressing cells, long-term treatment (24-48 h) with LUF7244 (10 μM) and dofetilide (1 μM) increased IKv11.1 compared to non-treated, or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of LUF7244 and an IKV11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects.SIGNIFICANCE STATEMENT LUF7244, a negative allosteric modulator/activator, in combination with dofetilide corrected both congenital and acquired Kv11.1 trafficking defects resulting in functional Kv11.1 current.