Proposed metabotropic mechanism for Ca
2+ signaling in HEK293 cells underlying the modulation of some of the cellular responses induced by Echinacea extracts. Green arrows indicate steps proposed from data in this paper. Purple lines indicate inhibitors used in this study. In this model, lipophilic constituents in Echinacea extracts bind to unidentified surface membrane receptor(s) (R), resulting in the activation of PLC. PLC-activation catalyzes the production of IP3 from PIP2. IP3 binds to and opens IP3R in the membrane of the ER, resulting in the release of Ca2+ from ER Ca2+ store. The decrease in the Ca2+ content of the ER is sensed by STIM1, which in turn activates SOCE in the plasma membrane. Thus, the level of cytosolic Ca2+ is increased through release of Ca2+ from the ER Ca2+ store as well as Ca2+ influx via SOCE. Receptors endogenous to HEK293 cells include: chemokine receptor; muscarinic acetylcholine receptor; glutamate receptor; B2-bradykinin receptor; and P2X, P2Y purinergic receptors ; these represent candidates for interaction with Echinacea constituents. PLC: phospholipase C; IP3, inositol-1,4,5-trisphosphate; PIP2: phosphatidylinositol-4,5-bisphosphate; IP3R: IP3 receptor; ER: endoplasmic reticulum; STIM1: stromal interaction molecule 1; SOCE: store-operated calcium entry.