TY - JOUR
T1 - LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1
AU - Qile, Muge
AU - Ji, Yuan
AU - Golden, Tyona D
AU - Houtman, Marien J C
AU - Romunde, Fee
AU - Fransen, Doreth
AU - van Ham, Willem B
AU - IJzerman, Ad P
AU - January, Craig T
AU - Heitman, Laura H
AU - Stary-Weinzinger, Anna
AU - Delisle, Brian P
AU - van der Heyden, Marcel A G
N1 - Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2020/6
Y1 - 2020/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084379821&partnerID=8YFLogxK
U2 - 10.1124/mol.119.118190
DO - 10.1124/mol.119.118190
M3 - Article
C2 - 32241959
SN - 0026-895X
VL - 97
SP - 355
EP - 364
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 6
ER -