title: Homeostatic regulation of the PI(4,5)P2-Ca(2+) signaling system at ER-PM junctions.
abstract: The phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-Ca(2+) 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 Ca(2+) from the endoplasmic reticulum (ER) store to the cytosol to activate Ca(2+)-mediated responses, such as secretion and proliferation. The consumed PM PI(4,5)P2 and ER Ca(2+) must be quickly restored to sustain signaling responses, and to maintain the homeostasis of PI(4,5)P2 and Ca(2+). Since phosphatidylinositol (PI), the precursor lipid for PM PI(4,5)P2, is synthesized in the ER membrane, and a Ca(2+) influx across the PM is required to refill the ER Ca(2+) store, efficient communications between the ER and the PM are critical for the homeostatic regulation of the PI(4,5)P2-Ca(2+) signaling system. This review describes the major findings that established the framework of the PI(4,5)P2-Ca(2+) signaling system, and recent discoveries on feedback control mechanisms at ER-PM junctions that sustain the PI(4,5)P2-Ca(2+) 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-Ca(2+) signaling, including the ER Ca(2+) 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.
authors.affiliation: Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chi-Lun
authors.initials: CL
authors.lastname: Chang
authors.affiliation: Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Jen.Liou@UTSouthwestern.edu.
authors.forename: Jen
authors.initials: J
authors.lastname: Liou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D000071740:ORAI1 Protein; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: ER–PM junctions; ESyt1; Nir2; PI cycle; PI(4,5)P(2)–Ca(2+) signaling; SOCE