Tripterygium-derived celastrol inhibits 5-HT3A receptors via key residue interactions: A comparative electrophysiological and docking study

Abstract

This study examines the effects of three Tripterygium wilfordii compounds-celastrol, triptolide, and triptonide-on 5-HT3A receptors. Using two-electrode voltage-clamp recordings, we found all three compounds reversibly and concentration-dependently inhibited 5-HT-induced inward currents (I_5-HT), with celastrol showing the strongest inhibition (∼83 % at 100 µM) compared to triptolide (∼40 %) and triptonide (∼30 %) at 300 µM. Their voltage- and use-independent inhibition suggests they are not open-channel blockers. Further molecular docking and mutational analysis revealed celastrol binds to K127 and Y114, with mutations at these sites significantly reducing its inhibitory effect. Overall, celastrol, triptolide, and triptonide may suppress hyperactive gut signaling via 5-HT3A inhibition, with celastrol emerging as a promising therapeutic candidate.

Keywords: 5-HT3A receptor; Celastrol; Tripterygium wilfordii Hook F; Triptolide; Triptonide.