A STIM1-dependent 'trafficking trap' mechanism regulates Orai1 plasma membrane residence and Ca<sup>2+</sup> influx levels

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13 Citations (Scopus)

Abstract

The key proteins mediating store-operated Ca<sup>2+</sup> entry (SOCE) are the endoplasmic reticulum (ER) Ca<sup>2+</sup> sensor STIM1 and the plasma membrane Ca<sup>2+</sup>-selective channel Orai1. Here, we quantitatively dissect Orai1 trafficking dynamics and show that Orai1 recycles rapidly at the plasma membrane (K<inf>ex</inf>≃0.1 min<sup>-1</sup>), with ~40% of the total Orai1 pool localizing to the plasma membrane at steady state. A subset of intracellular Orai1 localizes to a sub-plasmalemal compartment. Store depletion is coupled to Orai1 plasma membrane enrichment in a STIM1-dependent fashion. This is due to trapping of Orai1 into cortical ER STIM1 clusters, leading to its removal from the recycling pool and enrichment at the plasma membrane. Interestingly, upon high STIM1 expression, Orai1 is trapped into STIM1 clusters intracellularly, thus preventing its plasma membrane enrichment following store depletion. Consistent with this, STIM1 knockdown prevents trapping of excess Orai1 into limiting STIM1 clusters in the cortical ER. SOCE-dependent Ca<sup>2+</sup> influx shows a similar biphasic dependence on the Orai1:STIM1 ratio. Therefore, a STIM1-dependent Orai1 'trafficking trap' mechanism controls Orai1 plasma membrane enrichment and SOCE levels, thus modulating the SOCE 'bandwidth' for downstream signaling.

Original languageEnglish
Pages (from-to)3143-3154
Number of pages12
JournalJournal of Cell Science
Volume128
Issue number15
DOIs
Publication statusPublished - 2015

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Cell Membrane
Endoplasmic Reticulum
Recycling
Proteins

Keywords

  • Orai1
  • STIM1
  • Store-operated Ca2+ entry
  • Trafficking

ASJC Scopus subject areas

  • Cell Biology

Cite this

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title = "A STIM1-dependent 'trafficking trap' mechanism regulates Orai1 plasma membrane residence and Ca2+ influx levels",
abstract = "The key proteins mediating store-operated Ca2+ entry (SOCE) are the endoplasmic reticulum (ER) Ca2+ sensor STIM1 and the plasma membrane Ca2+-selective channel Orai1. Here, we quantitatively dissect Orai1 trafficking dynamics and show that Orai1 recycles rapidly at the plasma membrane (Kex≃0.1 min-1), with ~40{\%} of the total Orai1 pool localizing to the plasma membrane at steady state. A subset of intracellular Orai1 localizes to a sub-plasmalemal compartment. Store depletion is coupled to Orai1 plasma membrane enrichment in a STIM1-dependent fashion. This is due to trapping of Orai1 into cortical ER STIM1 clusters, leading to its removal from the recycling pool and enrichment at the plasma membrane. Interestingly, upon high STIM1 expression, Orai1 is trapped into STIM1 clusters intracellularly, thus preventing its plasma membrane enrichment following store depletion. Consistent with this, STIM1 knockdown prevents trapping of excess Orai1 into limiting STIM1 clusters in the cortical ER. SOCE-dependent Ca2+ influx shows a similar biphasic dependence on the Orai1:STIM1 ratio. Therefore, a STIM1-dependent Orai1 'trafficking trap' mechanism controls Orai1 plasma membrane enrichment and SOCE levels, thus modulating the SOCE 'bandwidth' for downstream signaling.",
keywords = "Orai1, STIM1, Store-operated Ca2+ entry, Trafficking",
author = "Rawad Hodeify and Senthil Selvaraj and Jennifer Wen and Abdelilah Arredouani and Hubrack, {Satanay Zuhair} and Maya Dib and Al-Thani, {Sara N.} and Timothy McGraw and Khaled Machaca",
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T1 - A STIM1-dependent 'trafficking trap' mechanism regulates Orai1 plasma membrane residence and Ca2+ influx levels

AU - Hodeify, Rawad

AU - Selvaraj, Senthil

AU - Wen, Jennifer

AU - Arredouani, Abdelilah

AU - Hubrack, Satanay Zuhair

AU - Dib, Maya

AU - Al-Thani, Sara N.

AU - McGraw, Timothy

AU - Machaca, Khaled

PY - 2015

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N2 - The key proteins mediating store-operated Ca2+ entry (SOCE) are the endoplasmic reticulum (ER) Ca2+ sensor STIM1 and the plasma membrane Ca2+-selective channel Orai1. Here, we quantitatively dissect Orai1 trafficking dynamics and show that Orai1 recycles rapidly at the plasma membrane (Kex≃0.1 min-1), with ~40% of the total Orai1 pool localizing to the plasma membrane at steady state. A subset of intracellular Orai1 localizes to a sub-plasmalemal compartment. Store depletion is coupled to Orai1 plasma membrane enrichment in a STIM1-dependent fashion. This is due to trapping of Orai1 into cortical ER STIM1 clusters, leading to its removal from the recycling pool and enrichment at the plasma membrane. Interestingly, upon high STIM1 expression, Orai1 is trapped into STIM1 clusters intracellularly, thus preventing its plasma membrane enrichment following store depletion. Consistent with this, STIM1 knockdown prevents trapping of excess Orai1 into limiting STIM1 clusters in the cortical ER. SOCE-dependent Ca2+ influx shows a similar biphasic dependence on the Orai1:STIM1 ratio. Therefore, a STIM1-dependent Orai1 'trafficking trap' mechanism controls Orai1 plasma membrane enrichment and SOCE levels, thus modulating the SOCE 'bandwidth' for downstream signaling.

AB - The key proteins mediating store-operated Ca2+ entry (SOCE) are the endoplasmic reticulum (ER) Ca2+ sensor STIM1 and the plasma membrane Ca2+-selective channel Orai1. Here, we quantitatively dissect Orai1 trafficking dynamics and show that Orai1 recycles rapidly at the plasma membrane (Kex≃0.1 min-1), with ~40% of the total Orai1 pool localizing to the plasma membrane at steady state. A subset of intracellular Orai1 localizes to a sub-plasmalemal compartment. Store depletion is coupled to Orai1 plasma membrane enrichment in a STIM1-dependent fashion. This is due to trapping of Orai1 into cortical ER STIM1 clusters, leading to its removal from the recycling pool and enrichment at the plasma membrane. Interestingly, upon high STIM1 expression, Orai1 is trapped into STIM1 clusters intracellularly, thus preventing its plasma membrane enrichment following store depletion. Consistent with this, STIM1 knockdown prevents trapping of excess Orai1 into limiting STIM1 clusters in the cortical ER. SOCE-dependent Ca2+ influx shows a similar biphasic dependence on the Orai1:STIM1 ratio. Therefore, a STIM1-dependent Orai1 'trafficking trap' mechanism controls Orai1 plasma membrane enrichment and SOCE levels, thus modulating the SOCE 'bandwidth' for downstream signaling.

KW - Orai1

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