Mechanism of hERG channel block by the psychoactive indole alkaloid ibogaine.
The Journal of pharmacology and experimental therapeutics – February 01, 2014
Source: PubMed
Summary
A crucial insight reveals why ibogaine, a substance explored for addiction treatment, can dangerously disrupt heart rhythm. Scientists found that ibogaine blocks hERG channels, key heart proteins, from inside the cell, primarily when these channels are active. The drug's impact varies with acidity and shifts how the channel opens and closes. Mutations in the channel's binding site reduced ibogaine's potency, while computer models confirmed binding within its inner cavity. These findings illuminate how ibogaine alters the heart's electrical balance by changing channel states.
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.