Ginsenoside Rd Activates Ciliary Beat Frequency via Estrogen Receptor β and P2X7 Receptor

Basal cells, goblet cells, and ciliated cells compose the human airway epithelium and protect the respiratory tract from foreign substances through their involvement in mucociliary clearance (MCC). In particular, ciliary beat frequency (CBF) is an important indicator of MCC efficiency. Although several herbal medicines have been reported to increase CBF, it is still unclear which compounds in these medicines are responsible for this effect. In the present study, we performed experiments to identify compounds that directly increase CBF and elucidated their mechanisms of action. We screened ginsenosides and their derivatives owned by Kyoto Pharmaceutical University and found that ginsenoside Rd was the most effective in increasing CBF and intracellular cAMP concentration ([cAMP]_i). Furthermore, we identified the estrogen receptor β (ERβ) as a new target of ginsenoside Rd-mediated increases in [cAMP]_i and CBF. We also found that ginsenoside Rd increased [Ca²⁺]_i and potentiated the positive effect of ATP on CBF by acting as a positive allosteric modulator (PAM) for the P2X7 receptor in murine airway ciliated cells. In conclusion, the results suggest that ginsenoside Rd increases CBF and that its mechanism of action is as an agonist of ERβ and a PAM of the P2X7 receptor.