title: The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters.
abstract: Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study.
authors.affiliation: Center of Physiology and Pharmacology, Medical University Vienna, Vienna, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Bulling
authors.forename: Klaus
authors.initials: K
authors.lastname: Schicker
authors.forename: Yuan-Wei
authors.initials: YW
authors.lastname: Zhang
authors.forename: Thomas
authors.initials: T
authors.lastname: Steinkellner
authors.forename: Thomas
authors.initials: T
authors.lastname: Stockner
authors.forename: Christian W
authors.initials: CW
authors.lastname: Gruber
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehm
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.forename: Gary
authors.initials: G
authors.lastname: Rudnick
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.forename: Walter
authors.initials: W
authors.lastname: Sandtner
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007050:Ibogaine / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D018408:Patch-Clamp Techniques; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D007050:Ibogaine