Homeostatic regulation of the PI(4,5)P₂-Ca²⁺ signaling system at ER-PM junctions

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 occur, 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 article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.