Proceedings of the National Academy of Sciences
March 1, 1992
Gary Rudnick, S C Wall
533 citations
MDMA (ecstasy) acts on serotonin transporters in both the plasma membrane and secretory vesicles. In plasma membrane vesicles from human platelets, MDMA inhibits serotonin transport and imipramine binding by directly interacting with the sodium-dependent serotonin transporter, and it stimulates serotonin efflux in a stereo-specific, sodium-dependent, and imipramine-sensitive manner via transporter-mediated exchange. In vesicles from bovine adrenal chromaffin granules containing the vesicular biogenic amine transporter, MDMA inhibits ATP-dependent serotonin accumulation and stimulates efflux by dissipating the transmembrane pH difference and directly interacting with the vesicular transporter.
The Journal of biological chemistry
October 5, 2007
Miriam T Jacobs, Yuan-Wei Zhang, Scott D Campbell et al.
149 citations
Ibogaine, a hallucinogenic alkaloid reported to help treat addiction, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, reducing the maximum transport rate (Vmax) with little effect on serotonin's binding affinity (Km). It also competitively blocks binding of a cocaine analog to SERT, increasing the apparent dissociation constant (KD) without altering the number of binding sites (Bmax). Ibogaine increases reactivity of cysteine residues in the proposed cytoplasmic permeation pathway of SERT but slows reactivity of cysteines in the extracellular pathway. These findings suggest ibogaine binds to and stabilizes the SERT state from which serotonin dissociates into the cytoplasm, opposite to cocaine's action, which stabilizes the state that binds extracellular serotonin.
The Journal of biological chemistry
May 25, 2012
Simon Bulling, Klaus Schicker, Yuan-Wei Zhang et al.
124 citations
Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, unlike all other known inhibitors which compete with serotonin. It binds to a distinct site accessible from the cell exterior, not the substrate-binding site, and increases accessibility in the cytoplasmic permeation pathway. Ibogaine also noncompetitively inhibits the dopamine transporter (DAT) and blocks substrate-induced currents in both transporters. The inhibition is not reversed by increasing substrate concentration, and ibogaine does not form a long-lived complex with SERT but binds directly to the inward-open conformation. A kinetic model distinguishes ibogaine's noncompetitive action from cocaine's competitive action.
Cell
May 11, 2023
Isha Singh, Anubha Seth, Christian B Billesbølle et al.
97 citations
Docking over 200 million small molecules against the inward-open state of the serotonin transporter (SERT) identified two potent, low-nanomolar inhibitors that stabilize an outward-closed conformation. These compounds showed little activity against common off-targets, and a cryo-EM structure confirmed the predicted binding geometry. In mouse behavioral assays, both compounds exhibited anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold greater than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects. The work suggests a promising path toward new treatments for depression, anxiety, and addiction with improved safety.
Proceedings of the National Academy of Sciences of the United States of America
May 17, 2016
Yuan-Wei Zhang, Benjamin E Turk, Gary Rudnick
53 citations
The serotonin transporter (SERT) clears serotonin from synapses, and mutations in human SERT are linked to psychiatric disorders and autism. Phosphorylation at a specific site, threonine 276 near the cytoplasmic end of transmembrane helix 5, regulates SERT activity. Agents that stabilize the outward-open conformation of SERT, such as sodium ions and cocaine, decrease phosphorylation, while agents that stabilize the inward-open conformation, such as serotonin and ibogaine, increase phosphorylation. The opposing effects of cocaine and ibogaine are reversible by an excess of the other inhibitor. These findings suggest that serotonin transport itself activates a regulatory mechanism, possibly involving unwinding of the helix to allow phosphorylation.
bioRxiv Preprint Server
June 13, 2022
Isha Singh, Anubha Seth, Christian B. Billesbølle et al.
8 citations
preprint
The serotonin transporter (SERT) adopts three conformations, and most antidepressants target its outward-open state. Ibogaine, which targets the inward-open state, has an unusual antidepressant profile but is cardiotoxic. Computational docking of over 200 million small molecules against the ibogaine-stabilized inward-open SERT identified 36 top compounds; 13 inhibited SERT with potencies from 29 to 5000 nM. Optimization yielded two inhibitors with Ki values as low as 3 nM that stabilized an outward-closed state and showed little off-target activity. A cryo-EM structure confirmed the predicted binding geometry. In mice, both compounds showed anxiolytic and antidepressant activity with potencies up to 200 times greater than fluoxetine.