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Mutations and post-translational modifications that disrupt ORAI-driven calcium homeostasis contribute to immune disorders, myopathy, cardiovascular diseases, and cancers. The review summarizes how small-molecule ORAI targeting modulates calcium signaling, and how optogenetics and optochemistry enable more precise regulation. It also highlights advanced optical tools, inhibitors, and antibodies, linking ORAI modulation to cancer initiation, progression, and therapeutic research.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/orai-ca2-channels-in-cancers-and-therapeutic-interventions-review/330492/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/orai-ca2-channels-in-cancers-and-therapeutic-interventions-review/330492.png","ImageObject",300,407,{"name":92,"@type":93},"Emma Wilson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-12","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role do ORAI proteins play in cellular calcium signaling?","Question",{"text":112,"@type":113},"ORAI proteins form the pore-forming subunits of CRAC channels and gate calcium entry downstream of store depletion via the STIM1-mediated pathway.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How can ORAI dysfunction contribute to cancer?",{"text":117,"@type":113},"Disrupted ORAI-dependent calcium homeostasis affects pathways underlying cancer-related processes such as proliferation, migration, and transformation, thereby influencing initiation and progression.",{"name":119,"@type":110,"acceptedAnswer":120},"What therapeutic strategies target ORAI channels?",{"text":121,"@type":113},"The review discusses small molecules as well as emerging approaches such as optogenetics and optochemistry, including advanced optical tools, pharmacological inhibitors, and antibodies for ORAI modulation.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},330492,1791185532,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},3848291630094,"https://eur-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","biomolecules  \nReview  \nORAI Ca2+ Channels in Cancers and Therapeutic Interventions  \nQian Zhang †, Chen Wang † and Lian He *  \nCitation: Zhang, Q.; Wang, C.; He, L. ORAI Ca2+ Channels in Cancers and Therapeutic Interventions. Biomolecules 2024, 14, 417. [https://](https://)  \n[doi.org/10.3390/biom14040417](doi.org/10.3390/biom14040417)[ ](doi.org/10.3390/biom14040417)Academic Editor: Jonathan Soboloff  \nReceived: 29 February 2024  \nRevised: 26 March 2024  \nAccepted: 27 March 2024  \nPublished: 29 March 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nDepartment of Pharmacology, Joint Laboratory of Guangdong–Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; [zhangq8@sustech.edu.cn](zhangq8@sustech.edu.cn) (Q.Z.); [lnaswc@foxmail.com](lnaswc@foxmail.com) (C.W.)  \n* [Correspondence: hel3@sustech.edu.cn](Correspondence: hel3@sustech.edu.cn)  \n† These authors contributed equally to this work.  \nAbstract: 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.  \nKeywords: CRAC channels; store-operated Ca2+ entry; ORAI; optogenetics; cancers  \n1. Introduction  \nThe majority of cellular activities, including but not limited to cell proliferation [1], migration [2], transformation [3], and mitophagy [4], utilize Ca2+ as a second messenger. Dysfunction of Ca2+ regulation can lead to various diseases, especially cancers. In non-excitable cells, store-operated Ca2+ entry (SOCE) is one of the most common routes mediating Ca2+ influx. It is triggered by the depletion of intracellular Ca2+ stores and subsequently activates stromal interaction molecule (STIM), an endoplasmic reticulum (ER)-resident Ca2+ sensor. STIM then gates and opens cell-membrane-localized ORAI Ca2+ channels [5] .  \nThe ORAI family consists of three highly conserved homologous subtypes: ORAI1, ORAI2, and ORAI3 (Figure 1A) . ORAI1 and ORAI2 in vertebrates evolved from the single ORAI protein in invertebrates, and the duplication of the Orai1 gene led to ORAI3 in mammals. They are uniformly distributed in the plasma membrane, but the function of ORAI1 is much better known compared to the other two. Each ORAI protein has four transmembrane domains (TM1–4) connected by one intracellular and two extracellular loops, with both N-and C-termini facing the cytoplasm (Figure 1B) . They are all involved in store-operated STIM1-mediated activation with high Ca2+ selectivity, yet they possess distinct functional and structural characteristics. While the transmembrane domains in ORAI homologs exhibit approximately 80% sequence identity, notable variations in sequence are evident within the cytosolic","cbCaiixc5EgXZtRW","https://ap.wps.com/l/cbCaiixc5EgXZtRW","pdf",2034761,17,"English","# Introduction\n## ORAI family and CRAC channel activation\n## ORAI isoforms, structure, and functional differences\n## Pharmacological profiles and therapeutic modulation","[{\"question\":\"What role do ORAI proteins play in cellular calcium signaling?\",\"answer\":\"ORAI proteins form the pore-forming subunits of CRAC channels and gate calcium entry downstream of store depletion via the STIM1-mediated pathway.\"},{\"question\":\"How can ORAI dysfunction contribute to cancer?\",\"answer\":\"Disrupted ORAI-dependent calcium homeostasis affects pathways underlying cancer-related processes such as proliferation, migration, and transformation, thereby influencing initiation and progression.\"},{\"question\":\"What therapeutic strategies target ORAI channels?\",\"answer\":\"The review discusses small molecules as well as emerging approaches such as optogenetics and optochemistry, including advanced optical tools, pharmacological inhibitors, and antibodies for ORAI modulation.\"}]","ORAI Ca2+ Channels in Cancers and Therapeutic Interventions - Review | PDF",1789989154,43]