Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2+

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Abstract

Loss of endoplasmic reticular (ER) Ca²⁺ activates store-operated Ca²⁺ entry (SOCE) by causing the ER localized Ca²⁺sensor STIM to unfurl domains that activate Orai channels in the plasma membrane at membrane contact sites (MCS). Here we demonstrate a novel mechanism by which the inositol 1,4,5 trisphosphate receptor (IP₃R), an ER-localized IP₃-gated Ca²⁺ channel, regulates neuronal SOCE. In human neurons, SOCE evoked by pharmacological depletion of ER-Ca²⁺ is attenuated by loss of IP₃Rs, and restored by expression of IP₃Rs even when they cannot release Ca²⁺, but only if the IP₃Rs can bind IP₃. Imaging studies demonstrate that IP₃Rs enhance association of STIM1 with Orai1 in neuronal cells with empty stores; this requires an IP₃-binding site, but not a pore. Convergent regulation by IP₃Rs, may tune neuronal SOCE to respond selectively to receptors that generate IP₃.

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The data supporting the findings of this study are available within the manuscript. All other data supporting the findings of this study are available in source data file of respective figures.

Article and author information

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Pragnya Chakraborty

Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bangalore, India

Competing interests
No competing interests declared.
Bipan Kumar Deb

Department of Molecular and Cell Biology, University of California, Berkeley, California, United States

Competing interests
No competing interests declared.
Vikas Arige

Department of Pharmacology and Physiology, University of Rochester, Rochester, United States

Competing interests
No competing interests declared.
Thasneem Musthafa

Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bangalore, India

Competing interests
No competing interests declared.
Sundeep Malik

Department of Pharmacology and Physiology, University of Rochester, Rochester, United States

Competing interests
No competing interests declared.
David I Yule

Department of Pharmacology and Physiology, University of Rochester, Rochester, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-6743-0668
Colin W Taylor

Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom

For correspondence
cwt1000@cam.ac.uk

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7771-1044
Gaiti Hasan

Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bangalore, India

For correspondence
gaiti@ncbs.res.in

Competing interests
Gaiti Hasan, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-7194-383X

Funding

Department of Science and Technology, Ministry of Science and Technology, India (DST/INSPIRE Fellowship/2017/IF170360)

Pragnya Chakraborty

Department of Biotechnology, Ministry of Science and Technology, India (BT/PR6371/COE/34/19/2013)

Gaiti Hasan

Tata Institute of Fundamental Research (NCBS,TIFR core support)

Gaiti Hasan

Wellcome Trust (101844)

Colin W Taylor

Biotechnology and Biological Sciences Research Council (BB/T012986/1)

Colin W Taylor

NIH (DE014756)

David I Yule

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.