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Nat Commun. 2017 Nov 15;8(1):1505. doi: 10.1038/s41467-017-01644-8.

Ca2+ signals initiate at immobile IP3 receptors adjacent to ER-plasma membrane junctions.

Author information

1
Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK.
2
Cactus Communications Pvt Ltd, 510 Shalimar Morya Park, Andheri (West), Mumbai, 400053, India.
3
Cairn Research Ltd, Graveney Road, Faversham, Kent, ME13 8UP, UK.
4
Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK. dp350@cam.ac.uk.
5
Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK. cwt1000@cam.ac.uk.

Abstract

IP3 receptors (IP3Rs) release Ca2+ from the ER when they bind IP3 and Ca2+. The spatial organization of IP3Rs determines both the propagation of Ca2+ signals between IP3Rs and the selective regulation of cellular responses. Here we use gene editing to fluorescently tag endogenous IP3Rs, and super-resolution microscopy to determine the geography of IP3Rs and Ca2+ signals within living cells. We show that native IP3Rs cluster within ER membranes. Most IP3R clusters are mobile, moved by diffusion and microtubule motors. Ca2+ signals are generated by a small population of immobile IP3Rs. These IP3Rs are licensed to respond, but they do not readily mix with mobile IP3Rs. The licensed IP3Rs reside alongside ER-plasma membrane junctions where STIM1, which regulates store-operated Ca2+ entry, accumulates after depletion of Ca2+ stores. IP3Rs 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.

PMID:
29138405
PMCID:
PMC5686115
DOI:
10.1038/s41467-017-01644-8
[Indexed for MEDLINE]
Free PMC Article

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