Orai1-KO Mouse

Orai1 is a key component of the store-operated Ca2+ release activated Ca2+ (CRAC) channel. It resides in the plasma membrane and, together with STIM1 in the endoplasmic reticulum-membrane, forms a highly Ca2+ selective ion channel complex. This complex is crucial for Ca2+ entry into non-excitable cells, which initiates diverse signalling cascades affecting processes like gene regulation, cell growth and death, secretion, and gene transcription [1].

In animal models of acute kidney injury (AKI), Orai1 is upregulated on lymphocytes. Inhibition of this channel attenuates both acute and chronic kidney injury in rodent models, suggesting it may be a new therapeutic target for the AKI-to-chronic kidney disease (CKD) transition. Also, in a rat model of ischemia/reperfusion, peripheral blood cells show an early and sustained increase in Orai1 expression, indicating that blood cell Orai1 may inform potential Th17 activity in AKI or the AKI-to-CKD transition [2]. In breast cancer cells, the interplay between Orai1 and adenylyl cyclase 8 (AC8) is important. AC8 overexpression in breast cancer cells impairs PKA-dependent Orai1α inactivation, contributing to enhanced store-operated Ca2+ entry (SOCE) [3]. In combined immunodeficiency, ORAI1 gene variations lead to clinical manifestations such as early-onset recurrent infection, congenital hypotonia, and abnormal immune cell counts. Most patients have a poor prognosis [4].

In conclusion, Orai1 is essential for Ca2+-dependent signalling pathways. Model-based research, especially in rodent models, has revealed its role in diseases like AKI-CKD transition, breast cancer, and combined immunodeficiency. Understanding Orai1's function provides potential therapeutic targets for these disease areas.

References:

1. Lunz, Victoria, Romanin, Christoph, Frischauf, Irene. 2018. STIM1 activation of Orai1. In Cell calcium, 77, 29-38. doi:10.1016/j.ceca.2018.11.009. https://pubmed.ncbi.nlm.nih.gov/30530091/

2. Basile, David P, Collett, Jason A. 2021. Orai1: A New Therapeutic Target for the Acute Kidney Injury-to-Chronic Kidney Disease Transition. In Nephron, 146, 264-267. doi:10.1159/000518177. https://pubmed.ncbi.nlm.nih.gov/34515158/

3. Sánchez-Collado, José, López, José J, Rosado, Juan A. 2021. The Orai1-AC8 Interplay: How Breast Cancer Cells Escape from Orai1 Channel Inactivation. In Cells, 10, . doi:10.3390/cells10061308. https://pubmed.ncbi.nlm.nih.gov/34070268/

4. Yang, H Y, Deng, X L, Yin, F, Peng, J, Wu, L W. . [ORAI1 variation induced combined immunodeficiency: a case report and literature review]. In Zhonghua er ke za zhi = Chinese journal of pediatrics, 57, 142-145. doi:10.3760/cma.j.issn.0578-1310.2019.02.015. https://pubmed.ncbi.nlm.nih.gov/30695890/