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 involved in gene regulation, cell growth and death, secretion, and gene transcription [1].

In animal models of acute kidney injury (AKI), Orai1 is upregulated on lymphocytes, especially Th17 cells. Inhibition of Orai1 attenuates both acute and chronic kidney injury in rodent models, suggesting its potential as a therapeutic target for the AKI-to-chronic kidney disease (CKD) transition [2]. In a case of combined immunodeficiency, a homozygous variation of the Orai1 gene led to clinical manifestations such as recurrent respiratory tract infections, congenital hypotonia, and abnormal immune cell counts. Most reported cases of Orai1-related combined immunodeficiency had a poor prognosis [3]. In breast cancer cells, the interplay between Orai1 and adenylyl cyclase 8 (AC8) affects the cAMP/PKA signalling and Orai1-dependent Ca2+ signals, with AC8 overexpression leading to impaired Orai1α inactivation and enhanced store-operated Ca2+ entry (SOCE) [4].

In conclusion, Orai1 is essential for Ca2+-mediated signalling pathways in various biological processes. Model-based research, especially in rodent models, has revealed its significant roles in diseases like AKI-CKD transition, combined immunodeficiency, and breast cancer. These findings highlight its potential as a therapeutic target and the importance of further research on Orai1 for understanding disease mechanisms and developing treatments.