Probing the Interaction Between Inactivation Gating and dd-Sotalol Block of HERG

Abstract—Potassium channels encoded by HERG underlie IKr, a sensitive target for most class III antiarrhythmic drugs, including methanesulfonanilides such as dd-sotalol. Recently it was shown that these drugs are trapped in the channel as it closes during hyperpolarization. At the same time, HERG channels rapidly open and inactivate when depolarized, and methanesulfonanilide block is known to develop in a use-dependent manner, suggesting a potential role for inactivation in drug binding. However, the role of HERG inactivation in class III drug action is uncertain: pore mutations that remove inactivation reduce block, yet many of these mutations also modify the channel permeation properties and could alter drug affinity through gating-independent mechanisms. In the present study, we identify a definitive role for inactivation gating in dd-sotalol block of HERG, using interventions complementary to mutagenesis. These interventions (addition of extracellular Cd2+, removal of extracellular Na+) modify the vol...