Role of STIM and Orai in Calcium Signaling

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (15 January 2024) | Viewed by 4939

Special Issue Editors


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Guest Editor
Secretory Physiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
Interests: calcium signalling; STIM; Orai1; membrane contact sites

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Guest Editor
Gottfried Schatz Research Center, Medical University of Graz, A-8010 Graz, Austria
Interests: calcium signaling; STIM; orai proteins
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Special Issue Information

Dear Colleagues,

Store-operated calcium entry (SOCE) refers to a mechanism whereby the Orai family of plasma membrane calcium channels is activated by a reduction in the endoplasmic reticulum (ER) Ca2+ stores, which is sensed by STIM1 and STIM2. The distinct Ca2+-binding affinities of the N-terminal EF hand of the STIM proteins underlie their ability to sense and respond to different stimulus intensities. In response to the release of Ca2+ from the luminal EF-hand domains, STIM proteins transition from a closed to an extended conformation, which exposes the SOAR domain which binds and gates the plasma membrane Orai channels. The STIMs and Orais assemble together in specialized membrane contact sites known as the ER–plasma membrane (ER–PM) junctions. Additionally, structural and scaffolding proteins that promote junctional stability and signaling proteins that modulate or regulate the function of Orai–STIM complexes are also assembled within these junctions. The concerted action between STIM proteins, Orai channels and a range of accessory proteins allows the cell to achieve precise spatio-temporal control of calcium signals that activate discrete downstream Ca2+-dependent signaling pathways. The scope of this Special Issue is to highlight recent developments that expand our current understanding of protein–protein and protein–lipid interactions that regulate Orai1–STIM complexes by utilizing a myriad of approaches that include the computational modelling of Ca2+ signals, molecular dynamic simulations, optogenetics, protein structure–function analysis and high-resolution imaging.

Dr. Hwei Ling Ong
Dr. Rainer Schindl
Guest Editors

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Keywords

  • store-operated calcium entry
  • STIM proteins
  • orai channels
  • membrane contact sites
  • spatio-temporation regulation of channel function
  • protein structure-function relationship

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Published Papers (3 papers)

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Research

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15 pages, 3640 KiB  
Article
Pregnancy-Specific Beta-1-Glycoprotein 1 Increases HTR-8/SVneo Cell Migration through the Orai1/Akt Signaling Pathway
by Qunhua Wang, Yan Fang, Yuan Li, Huali Liu, Maoni Zhu, Xue Hu, Jinzhuo Zhou, Anqi Deng, Bing Shen and Hongbo Chen
Biomolecules 2024, 14(3), 293; https://doi.org/10.3390/biom14030293 - 29 Feb 2024
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Abstract
The impaired invasion ability of trophoblast cells is related to the occurrence of preeclampsia (PE). We previously found that pregnancy-specific beta-1-glycoprotein 1 (PSG1) levels were decreased in the serum of individuals with early-onset preeclampsia (EOPE). This study investigated the effect of PSG1 on [...] Read more.
The impaired invasion ability of trophoblast cells is related to the occurrence of preeclampsia (PE). We previously found that pregnancy-specific beta-1-glycoprotein 1 (PSG1) levels were decreased in the serum of individuals with early-onset preeclampsia (EOPE). This study investigated the effect of PSG1 on Orai1-mediated store-operated calcium entry (SOCE) and the Akt signaling pathway in human trophoblast cell migration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the level of PSG1 in the serum of pregnant women with EOPE. The effects of PSG1 on trophoblast proliferation and migration were examined using cell counting kit-8 (CCK8) and wound healing experiments, respectively. The expression levels of Orai1, Akt, and phosphorylated Akt (p-Akt) were determined through Western blotting. The results confirmed that the serum PSG1 levels were lower in EOPE women than in healthy pregnant women. The PSG1 treatment upregulated the protein expression of Orai1 and p-Akt. The selective inhibitor of Orai1 (MRS1845) weakened the migration-promoting effect mediated by PSG1 via suppressing the Akt signaling pathway. Our findings revealed one of the mechanisms possibly involved in EOPE pathophysiology, which was that downregulated PSG1 may reduce the Orai1/Akt signaling pathway, thereby inhibiting trophoblast migration. PSG1 may serve as a potential target for the treatment and diagnosis of EOPE. Full article
(This article belongs to the Special Issue Role of STIM and Orai in Calcium Signaling)
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Review

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19 pages, 1779 KiB  
Review
A Deep Dive into the N-Terminus of STIM Proteins: Structure–Function Analysis and Evolutionary Significance of the Functional Domains
by Sasirekha Narayanasamy, Hwei Ling Ong and Indu S. Ambudkar
Biomolecules 2024, 14(10), 1200; https://doi.org/10.3390/biom14101200 - 24 Sep 2024
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Abstract
Calcium is an important second messenger that is involved in almost all cellular processes. Disruptions in the regulation of intracellular Ca2+ levels ([Ca2+]i) adversely impact normal physiological function and can contribute to various diseased conditions. STIM and Orai [...] Read more.
Calcium is an important second messenger that is involved in almost all cellular processes. Disruptions in the regulation of intracellular Ca2+ levels ([Ca2+]i) adversely impact normal physiological function and can contribute to various diseased conditions. STIM and Orai proteins play important roles in maintaining [Ca2+]i through store-operated Ca2+ entry (SOCE), with STIM being the primary regulatory protein that governs the function of Orai channels. STIM1 and STIM2 are single-pass ER-transmembrane proteins with their N- and C-termini located in the ER lumen and cytoplasm, respectively. The N-terminal EF-SAM domain of STIMs senses [Ca2+]ER changes, while the C-terminus mediates clustering in ER-PM junctions and gating of Orai1. ER-Ca2+ store depletion triggers activation of the STIM proteins, which involves their multimerization and clustering in ER-PM junctions, where they recruit and activate Orai1 channels. In this review, we will discuss the structure, organization, and function of EF-hand motifs and the SAM domain of STIM proteins in relation to those of other eukaryotic proteins. Full article
(This article belongs to the Special Issue Role of STIM and Orai in Calcium Signaling)
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17 pages, 1987 KiB  
Review
ORAI Ca2+ Channels in Cancers and Therapeutic Interventions
by Qian Zhang, Chen Wang and Lian He
Biomolecules 2024, 14(4), 417; https://doi.org/10.3390/biom14040417 - 29 Mar 2024
Cited by 1 | Viewed by 1651
Abstract
The ORAI proteins serve as crucial pore-forming subunits of calcium-release-activated calcium (CRAC) channels, pivotal in regulating downstream calcium-related signaling pathways. Dysregulated calcium homeostasis arising from mutations and post-translational modifications in ORAI can lead to immune disorders, myopathy, cardiovascular diseases, and even cancers. Small [...] Read more.
The ORAI proteins serve as crucial pore-forming subunits of calcium-release-activated calcium (CRAC) channels, pivotal in regulating downstream calcium-related signaling pathways. Dysregulated calcium homeostasis arising from mutations and post-translational modifications in ORAI can lead to immune disorders, myopathy, cardiovascular diseases, and even cancers. Small molecules targeting ORAI present an approach for calcium signaling modulation. Moreover, emerging techniques like optogenetics and optochemistry aim to offer more precise regulation of ORAI. This review focuses on the role of ORAI in cancers, providing a concise overview of their significance in the initiation and progression of cancers. Additionally, it highlights state-of-the-art techniques for ORAI channel modulation, including advanced optical tools, potent pharmacological inhibitors, and antibodies. These novel strategies offer promising avenues for the functional regulation of ORAI in research and may inspire innovative approaches to cancer therapy targeting ORAI. Full article
(This article belongs to the Special Issue Role of STIM and Orai in Calcium Signaling)
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