Biol. Cell (2011) 103, 365–380 (Printed in Great Britain) doi:10.1042/BC20100152 Review Remodelling of the endoplasmic reticulum during store-operated calcium entry Wei-Wei Shen, Maud Frieden and Nicolas Demaurex 1 Department of Cell Physiology and Metabolism, University of Geneva, 1 rue Michel-Servet CH-1211 Geneva 4, Switzerland SOCE (store-operated calcium entry) is a ubiquitous cellular mechanism linking the calcium depletion of the ER (endoplasmic reticulum) to the activation of PM (plasma membrane) Ca 2+ -permeable channels. The activation of SOCE channels favours the entry of extracellular Ca 2+ into the cytosol, thereby promoting the refilling of the depleted ER Ca 2+ stores as well as the generation of long-lasting calcium signals. The molecules that govern SOCE activation comprise ER Ca 2+ sensors [STIM1 (stromal interaction molecule 1) and STIM2], PM Ca 2+ -permeable channels {Orai and TRPC [TRP (transient receptor potential) canonical]} and regulatory Ca 2+ -sensitive cytosolic proteins {CRACR2 [CRAC (Ca 2+ release-activated Ca 2+ current) regulator 2]}. Upon Ca 2+ depletion of the ER, STIM molecules move towards the PM to bind and activate Orai or TRPC channels, initiating calcium entry and store refilling. This molecular rearrangement is accompanied by the formation of specialized compartments derived from the ER, the pre-cER (cortical ER) and cER. The pre-cER appears on the electron microscope as thin ER tubules enriched in STIM1 that extend along microtubules and that are devoid of contacts with the PM. The cER is located in immediate proximity to the PM and comprises thinner sections enriched in STIM1 and devoid of chaperones that might be dedicated to calcium signalling. Here, we review the molecular interactions and the morphological changes in ER structure that occur during the SOCE process. Introduction The ER (endoplasmic reticulum) plays a central role in cellular Ca 2+ homoeostasis by acting as the ma- jor intracellular store of Ca 2+ and by controlling the cytosolic entry of extracellular Ca 2+ ions across PM (plasma membrane) channels. Cellular Ca 2+ signals 1 To whom correspondence should be addressed (email Nicolas.Demaurex@unige.ch). Key words: calcium signalling, cell biology, endoplasmic reticulum, ion channels. Abbreviations used: BiP, binding immunoglobulin protein; CRAC, Ca 2+ release-activated Ca 2+ current; CAD, CRAC activation domain; CC1, first coiled-coil; cER, cortical ER; CIF, calcium influx factor; CMD, CRAC modulatory domain; COPI, coat protein complex I; CRACR2, CRAC regulator 2; DAG, diacylglycerol; EB1, end-binding protein-1; EM, electron microscopy; ER, endoplasmic reticulum; HEK-293 cells, human embryonic kidney cells; I CRAC , Ca 2+ release activated Ca 2+ current; IP 3 , inositol-1,4,5-trisphosphate; iPLA 2 , calcium-independent phospholipase A 2; Mfn2, mitofusin 2; PIP 2 , phosphatidylinositol-4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PM, plasma membrane; SCID, severe combined immunodeficiency; SAM, sterile α motif; SERCA, sarco/ER Ca 2+ -ATPase; SOCE, store-operated Ca 2+ entry; SOAR, STIM1 Orai activating region; STIM, stromal interaction molecule; SxIP, Ser-x-Ile-Pro; TAC, tip attachment complex; TM, transmembrane; TRP, transient receptor potential; TRPC, TRP canonical; YFP, yellow fluorescent protein. are initiated by the binding of physiological ligands to cell surface receptors that activate PLC (phospholi- pase C) to produce IP 3 (inositol-1,4,5-trisphosphate), a second messenger that rapidly releases Ca 2+ from the ER. The calcium release is transient due to the limited ER Ca 2+ storage capacity and is followed by a cytosolic influx of extracellular Ca 2+ across mem- brane channels, which sustains the calcium signal and enables the refilling of depleted stores. The Ca 2+ entry mechanism activated by the depletion of in- tracellular calcium stores was reported 25 years ago by Jim Putney (Putney, 1986; Putney et al., 1989) and the involvement of this ubiquitous SOCE (store- operated Ca 2+ entry; formerly known as capacitative Ca 2+ entry) in the generation of physiological and pathological cytosolic Ca 2+ signals is now well es- tablished (Parekh and Putney, 2005). SOCE sustains SOCE (store-operated calcium entry): Cellular mechanism linking the Ca 2+ depletion of the ER to the opening of PM Ca 2+ -permeable channels. www.biolcell.org | Volume 103 (8) | Pages 365–380 365 Biology of the Cell www.biolcell.org