title: Mechanism of hERG channel block by the psychoactive indole alkaloid ibogaine.
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.
authors.affiliation: Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria (H.G., V.S.G., K.H., S.B., X.K.), Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria (P.T., O.K., J.Z., W.S.), Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (A.S.-W.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Thurner
authors.forename: Anna
authors.initials: A
authors.lastname: Stary-Weinzinger
authors.forename: Hend
authors.initials: H
authors.lastname: Gafar
authors.forename: Vaibhavkumar S
authors.initials: VS
authors.lastname: Gawali
authors.forename: Oliver
authors.initials: O
authors.lastname: Kudlacek
authors.forename: Juergen
authors.initials: J
authors.lastname: Zezula
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Hilber
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
authors.forename: Walter
authors.initials: W
authors.lastname: Sandtner
authors.forename: Xaver
authors.initials: X
authors.lastname: Koenig
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006213:Hallucinogens / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007050:Ibogaine / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D050505:Mutant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; C000606913:KCNH2 protein, human; D049990:Membrane Transport Modulators; D050505:Mutant Proteins; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D007050:Ibogaine