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.
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.
Pharmaceuticals (Basel, Switzerland)
May 31, 2026
Wenting Zhang, Xin Guo, Jiping Zhang et al.
Combining the herbal formula Dajianzhong Decoction (DJZT) with ketamine produces synergistic antidepressant effects in a mouse model of depression. The combination restores levels of short-chain fatty acids (SCFAs), particularly acetic acid and isobutyric acid, in the gut. These SCFAs activate the FFAR2 receptor in the brain's medial prefrontal cortex, which suppresses NLRP3-IL-1β-driven neuroinflammation and reverses synaptic deficits. Blocking FFAR2 with the inhibitor GLPG0974 eliminates these benefits. The findings suggest that the SCFA-FFAR2-NLRP3-IL-1β axis mediates the prolonged antidepressant action of the combined treatment, pointing to microbiota-modulating strategies for improving ketamine therapy.