JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
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Ca 2+ signals initiate at immobile IP 3 receptors adjacent to ER-plasma membrane junctions.

Nature Communications 2017 November 16
IP3 receptors (IP3 Rs) release Ca2+ from the ER when they bind IP3 and Ca2+ . The spatial organization of IP3 Rs determines both the propagation of Ca2+ signals between IP3 Rs and the selective regulation of cellular responses. Here we use gene editing to fluorescently tag endogenous IP3 Rs, and super-resolution microscopy to determine the geography of IP3 Rs and Ca2+ signals within living cells. We show that native IP3 Rs cluster within ER membranes. Most IP3 R clusters are mobile, moved by diffusion and microtubule motors. Ca2+ signals are generated by a small population of immobile IP3 Rs. These IP3 Rs are licensed to respond, but they do not readily mix with mobile IP3 Rs. The licensed IP3 Rs reside alongside ER-plasma membrane junctions where STIM1, which regulates store-operated Ca2+ entry, accumulates after depletion of Ca2+ stores. IP3 Rs tethered close to ER-plasma membrane junctions are licensed to respond and optimally placed to be activated by endogenous IP3 and to regulate Ca2+ entry.

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