Ibogaine, a Noncompetitive Inhibitor of Serotonin Transport, Acts by Stabilizing the Cytoplasm-facing State of the Transporter

Summary

Ibogaine inhibits the serotonin transporter (SERT) noncompetitively by decreasing V(max) with minimal effect on K(m) for serotonin. It also competitively inhibits binding of a cocaine analog, increasing the apparent K(D). Ibogaine enhances reactivity of cysteine residues in the cytoplasmic pathway of SERT but not in the extracellular pathway. These findings suggest ibogaine stabilizes a state of SERT that allows serotonin to dissociate into the cytoplasm, contrasting with cocaine's effects.

Study at a glance

Abstract

Ibogaine, a hallucinogenic alkaloid with purported anti-addiction properties, inhibited serotonin transporter (SERT) noncompetitively by decreasing V(max) with little change in the K(m) for serotonin (5-HT). Ibogaine also inhibited binding to SERT of the cocaine analog 2beta-2-carbomethoxy-3-(4-[(125)I]iodophenyl)tropane. However, inhibition of binding was competitive, increasing the apparent K(D) without much change in B(max). 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.

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