Homeostatic Regulation of the PI(45)P2-Ca2+ Signaling System at ER-PM Junctions

摘要

The phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-Ca²⁺ signaling system is important for cell activation in response to various extracellular stimuli. This signaling system is initiated by receptor-induced hydrolysis of PI(4,5)P2 in the plasma membrane (PM) to generate the soluble second messenger inositol 1,4,5-trisphosphate (IP3). IP3 subsequently triggers the release of Ca²⁺ from the endoplasmic reticulum (ER) store to the cytosol to activate Ca²⁺-mediated responses, such as secretion and proliferation. The consumed PM PI(4,5)P2 and ER Ca²⁺ must be quickly restored to sustain signaling responses, and to maintain the homeostasis of PI(4,5)P2 and Ca²⁺. Since phosphatidylinositol (PI), the precursor lipid for PM PI(4,5)P2, is synthesized in the ER membrane, and a Ca²⁺ influx across the PM is required to refill the ER Ca²⁺ store, efficient communications between the ER and the PM are critical for the homeostatic regulation of the PI(4,5)P2-Ca²⁺ signaling system. This review describes the major findings that established the framework of the PI(4,5)P2-Ca²⁺ signaling system, and recent discoveries on feedback control mechanisms at ER-PM junctions that sustain the PI(4,5)P2-Ca²⁺ signaling system. Particular emphasis is placed on the characterization of ER-PM junctions where efficient communications between the ER and the PM occurs, and the activation mechanisms of proteins that dynamically localize to ER-PM junctions to provide the feedback control during PI(4,5)P2-Ca²⁺ signaling, including the ER Ca²⁺ sensor STIM1, the extended synaptotagmin E-Syt1, and the PI transfer protein Nir2. This review is part of a Special Issue entitled The Cellular Lipid Landscape.