Orai3 is a member of the Orai channel family, unique to mammals and apparently evolved from Orai1. It plays a crucial role in calcium (Ca2+) signaling, participating in two independent Ca2+ currents: the store-operated current Icrac, involving interactions with STIM1/STIM2 and other Orai proteins, and the store-independent arachidonic acid (AA) or leukotriene C4-regulated current Iarc, involving Orai1 and STIM1 [1,2,3]. This regulation of Ca2+ influx is essential for numerous cellular processes such as cell proliferation, differentiation, and apoptosis [2]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In cancer, Orai3 overexpression has been linked to several hallmarks including cell cycle progression, proliferation, migration, and apoptosis resistance. For example, in estrogen receptor-positive breast cancer and non-small cell lung cancer cells, store-operated Ca2+ entry (SOCE) is highly dependent on Orai3, while in colorectal and pancreatic adenocarcinoma cells, it predominantly modulates SOCE. In prostate cancer cells, Orai3 forms Orai1/Orai3 heteromeric channels regulated by AA, reducing SOCE and enhancing proliferation [1]. In oral/oropharyngeal squamous cell carcinoma, Orai3 promotes cancer stemness by elevating ID1 expression [6]. However, in muscle-invasive bladder cancer, high Orai3 expression correlates with good prognosis [7]. In immune cells, studies using Orai3 -/- mice showed that ORAI3 is dispensable or redundant for physiological and pathological immune responses mediated by lymphocytes and macrophages, as deletion of Orai3 did not affect SOCE in B and T cells, and had normal effector functions in vitro and in vivo immune responses [5]. In pulmonary fibrosis, knockdown of Orai3 in BLM-induced lung fibrosis decreased fibroblast proliferation, ECM production, and activation of relevant signal pathways [4].

In summary, Orai3 is essential for Ca2+ signaling and is involved in multiple biological processes and disease conditions. Gene-knockout mouse models have revealed its role in cancer, immune responses, and pulmonary fibrosis, among others. Understanding Orai3's functions provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Sanchez-Collado, Jose, Jardin, Isaac, López, Jose J, Prevarskaya, Natalia, Rosado, Juan A. 2021. Role of Orai3 in the Pathophysiology of Cancer. In International journal of molecular sciences, 22, . doi:10.3390/ijms222111426. https://pubmed.ncbi.nlm.nih.gov/34768857/

2. Tanwar, Jyoti, Arora, Samriddhi, Motiani, Rajender K. 2020. Orai3: Oncochannel with therapeutic potential. In Cell calcium, 90, 102247. doi:10.1016/j.ceca.2020.102247. https://pubmed.ncbi.nlm.nih.gov/32659517/

3. Shuttleworth, Trevor J. 2011. Orai3--the 'exceptional' Orai? In The Journal of physiology, 590, 241-57. doi:10.1113/jphysiol.2011.220574. https://pubmed.ncbi.nlm.nih.gov/22041188/

4. Yu, Changhui, Zhou, Zicong, Huang, Wufeng, Meng, Xiaojing, Cai, Shaoxi. 2022. Orai3 mediates Orai channel remodelling to activate fibroblast in pulmonary fibrosis. In Journal of cellular and molecular medicine, 26, 4974-4985. doi:10.1111/jcmm.17516. https://pubmed.ncbi.nlm.nih.gov/36128650/

5. Wang, Liwei, Noyer, Lucile, Wang, Yin-Hu, Yang, Jun, Feske, Stefan. 2022. ORAI3 is dispensable for store-operated Ca2+ entry and immune responses by lymphocytes and macrophages. In The Journal of general physiology, 154, . doi:10.1085/jgp.202213104. https://pubmed.ncbi.nlm.nih.gov/35861698/

6. Nguyen, Anthony, Sung, Youngjae, Lee, Sung Hee, Kim, Yong, Shin, Ki-Hyuk. 2023. Orai3 Calcium Channel Contributes to Oral/Oropharyngeal Cancer Stemness through the Elevation of ID1 Expression. In Cells, 12, . doi:10.3390/cells12182225. https://pubmed.ncbi.nlm.nih.gov/37759448/

7. Yan, Jing, Yu, Wei, Lu, Chang, Jiang, Zizheng, Qin, Zheng. 2021. High ORAI3 expression correlates with good prognosis in human muscle-invasive bladder cancer. In Gene, 808, 145994. doi:10.1016/j.gene.2021.145994. https://pubmed.ncbi.nlm.nih.gov/34626722/