Mechanism of hERG channel block by the psychoactive indole alkaloid ibogaine.

Ibogaine, a psychoactive alkaloid used to treat addiction, can cause dangerous heart rhythm problems by blocking hERG potassium channels. Experiments on mammalian kidney cells expressing hERG channels showed that block occurred from either side of the cell membrane and depended on pH. Block happened only when channels were activated, not when resting. Stronger depolarizations increased block speed and extent. The drug shifted channel activation and inactivation to more negative voltages, slowed deactivation, and accelerated inactivation. Mutations Y652A and F656A reduced ibogaine's potency, but an inactivation-deficient mutant remained sensitive. Molecular docking suggested binding inside the channel cavity regardless of ibogaine's protonation state. Kinetic modeling indicated preferential binding to open and inactivated states.

Study at a glance

Abstract

Ibogaine is a psychoactive indole alkaloid. Its use as an antiaddictive agent has been accompanied by QT prolongation and cardiac arrhythmias, which are most likely caused by human ether a go-go-related gene (hERG) potassium channel inhibition. Therefore, we studied in detail the interaction of ibogaine with hERG channels heterologously expressed in mammalian kidney tsA-201 cells. Currents through hERG channels were blocked regardless of whether ibogaine was applied via the extracellular or intracellular solution. The extent of inhibition was determined by the relative pH values. Block occurred during activation of the channels and was not observed for resting channels. With increasing depolarizations, ibogaine block grew and developed faster. Steady-state activation and inactivation of the channel were shifted to more negative potentials. Deactivation was slowed, whereas inactivation was accelerated. Mutations in the binding site reported for other hERG channel blockers (Y652A and F656A) reduced the potency of ibogaine, whereas an inactivation-deficient double mutant (G628C/S631C) was as sensitive as wild-type channels. Molecular drug docking indicated binding within the inner cavity of the channel independently of the protonation of ibogaine. Experimental current traces were fit to a kinetic model of hERG channel gating, revealing preferential binding of ibogaine to the open and inactivated state. Taken together, these findings show that ibogaine blocks hERG channels from the cytosolic side either in its charged form alone or in company with its uncharged form and alters the currents by changing the relative contribution of channel states over time.