LUF7244 plus dofetilide rescues aberrant K_v11.1 trafficking and produces functional I_Kv11.1

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.