Two Lignan Glycosides from Albizia julibrissin Durazz. Noncompetitively Inhibit Serotonin Transporter

Abstract

Albizia julibrissin Durazz. is one of the most common herbs used for depression and anxiety treatment, but its molecular basis and mechanism of action as an antidepressant or anxiolytic drug are not understood. In this study, we separated and identified two lignan glycosides that inhibit serotonin transporter (SERT) noncompetitively by decreasing Vmax with little change in Km for its fluorescence substrate. In addition, treatment with lignan glycosides did not alter total and cell surface expression levels of the transporter protein. The two compounds decreased the accessibility of a cysteine residue placed in the extracellular substrate permeation pathway by inducing a conformational shift toward an outward-closed state of SERT. These results are consistent with molecular docking for the association of the lignan glycosides to the allosteric site in SERT. The present work supports the proposal that these compounds act on SERT by a novel underlying mechanism of action different from that of conventional antidepressant drugs.

Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters

“…Substrate 5-HT, which stabilizes the cytoplasmic-facing conformation of SERT in the presence of both Na + and Cl − (Forrest et al, 2008), significantly increased the reactivity of S277C, promoting its inactivation by MTSEA (Figures 3A,B, third image and second column from left, respectively), consistent with our previous observation that 5-HT induced conformational conversion from outward-facing to inward-facing (Huang et al, 2022). In contrast, fluoxetine, a SSRI, markedly decreased the reactivity of S277C, protecting it from MTSEA inactivation (Figures 3A,B, second image and second column from right, respectively).…”

“…Our previous study has demonstrated that SAG noncompetitively inhibited SERT activity ( Huang et al, 2022 ). To examine the possibility that SAG binds to the allosteric site, we conducted the molecular docking of SAG to hSERT, hDAT, and hNET on the hSERT structure and the hDAT and hNET models in an outward open conformation, respectively.…”

“…Our previous results showed that SAG strongly inhibited hSERT activity, but also weakly inhibited both hDAT and hNET (Huang et al, 2022). To explore the molecular mechanism of action of the herbal molecule by a structural approach, homology models for both hDAT and hNET were generated with Modeller based on an outward open structure of the Drosophila DAT (dDAT, PDB ID 4XP1).…”

“…We have recently isolated and identified two lignan glucosides, (-)-syringaresinol-4-O-D-apiofuranosyl-(1→2)-D-glucopyranoside (SAG) and (-)-syringaresinol-4,4′-bis-O-D-glucopyranoside (SBG), from the bark of Albizia julibrissin Durazz that acted on SERT by a novel underlying mechanism of action different from that of SSRIs ( Huang et al, 2022 ). Our previous results showed that the two lignan glycosides noncompetitively inhibited SERT activity and also induced a conformational shift toward an outward-closed state of the transporter protein.…”

“…Our previous results showed that the two lignan glycosides noncompetitively inhibited SERT activity and also induced a conformational shift toward an outward-closed state of the transporter protein. Thus, these compounds were proposed to directly bind to the transporter protein, presumably to the S2 site, thereby, to noncompetitively inhibit SERT activity by blocking essential conformational conversion for substrate transport ( Huang et al, 2022 ). Of these compounds, SAG is of special concern to study further because it has been demonstrated to exert an antidepressant and anxiolytic activity in acute restraint-stressed rat models in an earlier study, its molecular mechanism of action, however, was not uncovered ( Liu et al, 2017 ).…”