Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2+
- National Centre for Biological Sciences, India
- University of California, Berkeley, United States
- University of Rochester, United States
- University of Cambridge, United Kingdom
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.
Data availability
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
Author details
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.
Copyright
© 2023, Chakraborty et al.
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.
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Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2+
eLife 12:e80447.
https://doi.org/10.7554/eLife.80447
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