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Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels

Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca(2+) stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determi...

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Autores principales: Rana, Anshul, Yen, Michelle, Sadaghiani, Amir Masoud, Malmersjö, Seth, Park, Chan Young, Dolmetsch, Ricardo E., Lewis, Richard S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460148/
https://www.ncbi.nlm.nih.gov/pubmed/26033257
http://dx.doi.org/10.1083/jcb.201412060
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author Rana, Anshul
Yen, Michelle
Sadaghiani, Amir Masoud
Malmersjö, Seth
Park, Chan Young
Dolmetsch, Ricardo E.
Lewis, Richard S.
author_facet Rana, Anshul
Yen, Michelle
Sadaghiani, Amir Masoud
Malmersjö, Seth
Park, Chan Young
Dolmetsch, Ricardo E.
Lewis, Richard S.
author_sort Rana, Anshul
collection PubMed
description Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca(2+) stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determinants of Ca(2+)-dependent responses, the underlying modulatory mechanisms are unclear. In this paper, we identify STIM2β, a highly conserved alternatively spliced isoform of STIM2, which, in contrast to all known STIM isoforms, is a potent inhibitor of SOCE. Although STIM2β does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. Analysis of STIM2β mutants and Orai1-STIM2β chimeras suggested that it actively inhibits SOCE through a sequence-specific allosteric interaction with Orai1. Our results reveal a previously unrecognized functional flexibility in the STIM protein family by which alternative splicing creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals.
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spelling pubmed-44601482015-12-08 Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels Rana, Anshul Yen, Michelle Sadaghiani, Amir Masoud Malmersjö, Seth Park, Chan Young Dolmetsch, Ricardo E. Lewis, Richard S. J Cell Biol Research Articles Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca(2+) stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determinants of Ca(2+)-dependent responses, the underlying modulatory mechanisms are unclear. In this paper, we identify STIM2β, a highly conserved alternatively spliced isoform of STIM2, which, in contrast to all known STIM isoforms, is a potent inhibitor of SOCE. Although STIM2β does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. Analysis of STIM2β mutants and Orai1-STIM2β chimeras suggested that it actively inhibits SOCE through a sequence-specific allosteric interaction with Orai1. Our results reveal a previously unrecognized functional flexibility in the STIM protein family by which alternative splicing creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals. The Rockefeller University Press 2015-06-08 /pmc/articles/PMC4460148/ /pubmed/26033257 http://dx.doi.org/10.1083/jcb.201412060 Text en © 2015 Rana et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Rana, Anshul
Yen, Michelle
Sadaghiani, Amir Masoud
Malmersjö, Seth
Park, Chan Young
Dolmetsch, Ricardo E.
Lewis, Richard S.
Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels
title Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels
title_full Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels
title_fullStr Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels
title_full_unstemmed Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels
title_short Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels
title_sort alternative splicing converts stim2 from an activator to an inhibitor of store-operated calcium channels
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460148/
https://www.ncbi.nlm.nih.gov/pubmed/26033257
http://dx.doi.org/10.1083/jcb.201412060
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