The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions

doi:10.1083/jcb.200604015

Published 11 September 2006. doi:10.1083/jcb.200604015
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 6, 815-825

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The elementary unit of store-operated Ca²⁺ entry: local activation of CRAC channels by STIM1 at ER–plasma membrane junctions

Riina M. Luik, Minnie M. Wu, JoAnn Buchanan, and Richard S. Lewis

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305

Correspondence to Richard S. Lewis: rslewis{at}stanford.edu

The activation of store-operated Ca²⁺ entry by Ca²⁺ store depletionhas long been hypothesized to occur via local interactions ofthe endoplasmic reticulum (ER) and plasma membrane, but thestructure involved has never been identified. Store depletioncauses the ER Ca²⁺ sensor stromal interacting molecule 1 (STIM1)to form puncta by accumulating in junctional ER located 10–25nm from the plasma membrane (see Wu et al. on p. 803 of thisissue). We have combined total internal reflection fluorescence(TIRF) microscopy and patch-clamp recording to localize STIM1and sites of Ca²⁺ influx through open Ca²⁺ release–activatedCa²⁺ (CRAC) channels in Jurkat T cells after store depletion.CRAC channels open only in the immediate vicinity of STIM1 puncta,restricting Ca²⁺ entry to discrete sites comprising a smallfraction of the cell surface. Orai1, an essential componentof the CRAC channel, colocalizes with STIM1 after store depletion,providing a physical basis for the local activation of Ca²⁺influx. These studies reveal for the first time that STIM1 andOrai1 move in a coordinated fashion to form closely apposedclusters in the ER and plasma membranes, thereby creating theelementary unit of store-operated Ca²⁺ entry.

Abbreviations used in this paper: 2-APB, 2-aminoethyldiphenylborate; Ca_o²⁺, extracellular Ca²⁺; [Ca²⁺]_i, intracellular freeCa²⁺ concentration; CRAC, Ca²⁺ release–activated Ca²⁺;IRM, interference reflection microscopy; SOC, store-operatedchannel; SOCE, store-operated Ca²⁺ entry; SR, sarcoplasmic reticulum;STIM1, stromal interacting molecule 1; TG, thapsigargin; TIRF,total internal reflection fluorescence.

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