Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter

Miriam T. Jacobs, Yuan Wei Zhang, Scott D. Campbell, Gary Rudnick

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Ibogaine, a hallucinogenic alkaloid with purported anti-addiction properties, inhibited serotonin transporter (SERT) noncompetitively by decreasing Vmax with little change in the Km for serotonin (5-HT). Ibogaine also inhibited binding to SERT of the cocaine analog 2β-2-carbomethoxy-3-(4-[125I]iodophenyl)tropane. However, inhibition of binding was competitive, increasing the apparent KD without much change in Bmax. Ibogaine increased the reactivity of cysteine residues positioned in the proposed cytoplasmic permeation pathway of SERT but not at nearby positions out of that pathway. In contrast, cysteines placed at positions in the extracellular permeation pathway reacted at slower rates in the presence of ibogaine. These results are consistent with the proposal that ibogaine binds to and stabilizes the state of SERT from which 5-HT dissociates to the cytoplasm, in contrast with cocaine, which stabilizes the state that binds extracellular 5-HT.

Original languageEnglish
Pages (from-to)29441-29447
Number of pages7
JournalJournal of Biological Chemistry
Volume282
Issue number40
DOIs
StatePublished - Oct 5 2007

Fingerprint

Dive into the research topics of 'Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter'. Together they form a unique fingerprint.

Cite this