Figure 8

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 [10]; 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.