Identification and molecular study on the interaction of Schisandrin C with human 5-HT_3A receptor

Schisandrin C (Sch C) is one of the main components of Schisandra chinensis (Schisandra). Since the olden times, Schisandra has been used as a traditional herbal medicine in Asia. Recent studies have shown that Schisandra is effective against irritable bowel syndrome (IBS) in an animal model and affects IBS through the 5-HT_3A pathway in the IBS rat model. However, there lacks fundamental research on the interaction of specific components of Schisandra with the 5-HT_3A receptor for the treatment of IBS. We hypothesized that a component of Schisandra binds to the 5-HT_3A receptor and identified Sch C via a screening work using two electrode-voltage clamps (TEVC). Thus, we aimed to elucidate the neuropharmacological actions between Sch C and the 5-HT_3A receptor at molecular and cellular levels. Co-treatment of Sch C with 5-HT inhibited I_5-HT in a reversible, concentrate-dependent, like-competition, and voltage-independent manner, and IC₅₀ values of Sch C. Besides, the main binding positions of Sch C were identified through 3D modeling and point mutation were V225A and V288Y on 5-HT_3A receptor. Thus, we suggest the potential of Sch C in treating IBS in a manner that suppresses excessive neuronal serotonin signaling in the synapse of sensory neurons and enterochromaffin (EC) cells. In conclusion, the results demonstrate the mechanism of interaction between Sch C and 5-HT_3A receptor and reveal Sch C as a novel antagonist.