Homeostatic regulation of the PI(4,5)P 2 –Ca 2+ signaling system at ER–PM junctions

Abstract

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.

ER-plasma membrane junctions: Why and how do we study them?

“…Selective depletion of PI at the ER membrane disrupted Nir2-mediated PM PIP 2 replenishment [147], suggesting that Nir2 transports PI from the ER to the PM for PIP 2 resynthesis after hydrolysis to support receptor activation and PIP 2 -dependent cellular processes. Thus, Nir2 and Nir3 are feedback regulators for PM PIP 2 homeostasis by detecting metabolic intermediates generated by PIP 2 hydrolysis, translocating to ER-PM junctions, and replenishing PM PIP 2 [150, 151]. Consistently, knockdown of Nir2 significantly affected PIP 2 -associated functions, including receptor-induced Ca 2+ signaling, epidermal growth factor (EGF) signaling, cell migration, and epithelial-mesenchymal transition (EMT) [146, 147, 152].…”

“…Similar to STIM1 and STIM2 that work in tandem in response to different levels of ER Ca 2+ depletion, Nir3 is more sensitive to PA production than Nir2 and maintains PM PIP 2 homeostasis during basal and mild receptor activation conditions [147]. Therefore, during intense receptor activation, STIM1/STIM2, E-Syt1, and Nir2/Nir3 can simultaneously localize at ER-PM junctions to contribute to homeostatic regulation of the PIP 2 -Ca 2+ signaling system [150] (Fig. 5).…”

Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum–plasma membrane contact sites consisting of three synaptotagmins

“…In eukaryotic cells, the endoplasmic reticulum (ER) runs throughout the cytoplasm, and is in physical contact with other organelles such as Golgi bodies, peroxisomes and the plasma membrane (PM). Such contact sites have increasingly attracted attention because of their generally important functions in cellular processes such as lipid transfer and Ca 2+ homeostasis (Prinz, 2014;Idevall-Hagren et al, 2015;Chang & Liou, 2016;Saheki et al, 2016;Yu et al, 2016;Wu et al, 2018;Lee et al, 2019).…”

Local PI(4,5)P2pool dynamics detected by the coincidence biosensor tubbyCT maintain the integrity of ER-PM junctions during PLC signaling

“…Enrichment of PI(4,5)P2 at ER-PM junctions has been postulated before (Maléth et al, 2014), however, direct evidence has not been provided so far (Chang and Liou, 2016).…”

“…Thus, the existence of PI(4,5)P2enriched microdomains at ER-PM junctions was proposed (Maléth et al, 2014). However, direct experimental evidence for such spatial enrichment is still lacking (reviewed e.g., by (Chang and Liou, 2016).…”