Positive allosteric modulator activity of ginsenosides is restricted to P2X7 and P2X4 receptors

Positive allosteric modulators of P2X7 receptors hold promise as host-directed immune enhancers in intracellular infections. We have previously reported the use of protopanaxadiol ginsenosides as positive allosteric modulators of human, rat and mouse P2X7 receptors plus human P2X4 receptors, however, the effect of ginsenosides on other P2X receptors is unknown. Here, we screened a range of ginsenosides and related glycosides at hP2X1, hP2X2 and hP2X3 receptors expressed in HEK-293 cells utilising a membrane potential assay. Our results demonstrate the utility of the membrane potential assay across all P2X receptors and the lack of significant potentiation of ATP-induced responses at hP2X1, hP2X2 and hP2X3 receptors by ginsenosides and related glycosides. We report that S-Rg3 also acts as a positive allosteric modulator at hP2X4 receptors in addition to hP2X7 receptors. This information is important for determining the selectivity of ginsenoside positive allosteric modulators for P2X7 and P2X4.