Orai2, a member of the store-operated calcium channel (SOCC) family, plays a crucial role in calcium-mediated signaling pathways. Store-operated calcium entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels, of which Orai2 can be a part, is vital for many physiological functions, including lymphocyte function, immune responses, and cell migration [3,6].

In various disease models, Orai2 has distinct effects. In TNFα/IL1α-stimulated astrocytes, Orai2 knockdown or knockout leads to increased prostaglandin E2 (PGE2) production, suggesting it modulates central nervous system (CNS) inflammation [1]. Orai2 deficiency in mice facilitates the colonization of Akkermansia muciniphila, attenuating experimental colitis [2]. In gastric cancer, Orai2 promotes tumorigenicity and metastasis through PI3K/Akt signaling and MAPK-dependent focal adhesion disassembly [4]. In breast cancer cells, Orai2 modulates SOCE and cell cycle progression, and its knockdown leads to cell cycle arrest at the G0-G1 phase [5]. In human neuroglioma cells, Orai2 down-regulation potentiates SOCE and decreases Aβ42 accumulation, potentially relevant to Alzheimer's disease [7]. In salivary glands, Orai2 is important for the development of early-stage postirradiation fibrosis, and inhibition of SOCE signaling blocks fibrosis in an Orai2-dependent manner [8].

In summary, Orai2 is essential in regulating calcium-mediated signaling, with significant implications in multiple disease areas such as CNS inflammation, colitis, cancer, Alzheimer's disease, and radiation-induced salivary gland fibrosis. Gene knockout models, especially in mice, have been instrumental in revealing these functions, providing valuable insights into potential therapeutic targets for these diseases.

References:

1. Nakajima, Hiroki, Fujita, Sayaka, Kakae, Masashi, Shirakawa, Hisashi, Kaneko, Shuji. 2022. Orai2 channel regulates prostaglandin E2 production in TNFα/IL1α-stimulated astrocytes. In Glia, 70, 1666-1680. doi:10.1002/glia.24188. https://pubmed.ncbi.nlm.nih.gov/35506586/

2. Yan, Jing, Yu, Wei, Lu, Chang, Jiang, Zizheng, Liang, Zhenghao. 2022. Orai2 deficiency attenutates experimental colitis by facilitating the colonization of Akkermansia muciniphila. In Genomics, 114, 110479. doi:10.1016/j.ygeno.2022.110479. https://pubmed.ncbi.nlm.nih.gov/36070824/

3. Rychkov, Grigori Y, Zhou, Fiona H, Adams, Melissa K, Ma, Linlin, Barritt, Greg J. 2021. Orai1- and Orai2-, but not Orai3-mediated ICRAC is regulated by intracellular pH. In The Journal of physiology, 600, 623-643. doi:10.1113/JP282502. https://pubmed.ncbi.nlm.nih.gov/34877682/

4. Wu, Shayi, Chen, Miao, Huang, Jiao, Guan, Xin-Yuan, Lam, Ka-On. 2020. ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly. In Cancer research, 81, 986-1000. doi:10.1158/0008-5472.CAN-20-0049. https://pubmed.ncbi.nlm.nih.gov/33310726/

5. Sanchez-Collado, Jose, Lopez, Jose J, Cantonero, Carlos, Salido, Gines M, Rosado, Juan A. 2021. Orai2 Modulates Store-Operated Ca2+ Entry and Cell Cycle Progression in Breast Cancer Cells. In Cancers, 14, . doi:10.3390/cancers14010114. https://pubmed.ncbi.nlm.nih.gov/35008277/

6. Vaeth, Martin, Yang, Jun, Yamashita, Megumi, Prakriya, Murali, Feske, Stefan. 2017. ORAI2 modulates store-operated calcium entry and T cell-mediated immunity. In Nature communications, 8, 14714. doi:10.1038/ncomms14714. https://pubmed.ncbi.nlm.nih.gov/28294127/

7. Scremin, Elena, Agostini, Mario, Leparulo, Alessandro, Greotti, Elisa, Fasolato, Cristina. 2020. ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells. In International journal of molecular sciences, 21, . doi:10.3390/ijms21155288. https://pubmed.ncbi.nlm.nih.gov/32722509/

8. Li, Honglin, Cao, Yubin, Zhao, Guile, Tang, Patrick Ming-Kuen, Li, Chunjie. 2024. ORAI2 is Important for the Development of Early-Stage Postirradiation Fibrosis in Salivary Glands. In International journal of radiation oncology, biology, physics, 121, 798-810. doi:10.1016/j.ijrobp.2024.09.047. https://pubmed.ncbi.nlm.nih.gov/39384103/