ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets

Abstract

The changes in intracellular free calcium (Ca2+) levels are one of the most widely regulators of cell function; therefore, calcium as a universal intracellular mediator is involved in very important human diseases and disorders. In many cells, Ca2+ inflow is mediated by store-operated calcium channels, and it is recognized that the store-operated calcium entry (SOCE) is mediated by the two partners: the pore-forming proteins Orai (Orai1-3) and the calcium store sensor, stromal interaction molecule (STIM1-2). Importantly, the Orai/STIM channels are involved in crucial cell signalling processes such as growth factors, neurotransmitters, and cytokines via interaction with protein tyrosine kinase coupled receptors and G protein-coupled receptors. Therefore, in recent years, the issue of Orai/STIM channels as a drug target in human diseases has received considerable attention. This review summarizes and highlights our current knowledge of the Orai/STIM channels in human diseases and disorders, including immunodeficiency, myopathy, tubular aggregate, Stormorken syndrome, York platelet syndrome, cardiovascular and metabolic disorders, and cancers, as well as suggesting these channels as drug targets for pharmacological therapeutic intervention. Moreover, this work will also focus on the pharmacological modulators of Orai/STIM channel complexes. Together, our thoughtful of the biology and physiology of the Orai/STIM channels have grown remarkably during the past three decades, and the next important milestone in the field of store-operated calcium entry will be to identify potent and selective small molecules as a therapeutic agent with the purpose to target human diseases and disorders for patient benefit.

Remodeling Ca2+dynamics by targeting a promising E-box containing G-quadruplex atORAI1promoter in triple-negative breast cancer

“…8 The calcium homeostasis that is maintained by ORAI1 is in a very integrated complex signaling cascade involving a lot of other cellular effectors. 50 ORAI1 might mediate its function through store-dependent or independent pathways by interaction with other factors overexpressed in cancer, like SPCA2. 51 However, though much has been extensively studied about the interaction pathways between the proteome and its subsequent role in cancer, 7 the transcription regulation of ORAI1 is still not extensively characterized.…”

The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration

“…Calcium-activated CaM binds to STIM near the C-terminal, disrupting the STIM/Orai interaction and shutting down calcium influx [33]. CaM also binds to the N-terminal of Orai proteins where it is involved in CDI of SOCE [21,159]. Orai/STIM SOCE is involved in numerous age-related neurodegenerative diseases including AD, HD, and PD [155,159].…”

A rare ORAI1 missense variant associates with risk of vascular diseases in White British adults

“…Here, we studied ORAI1 as a promising druggable candidate protein 17,18 for CVD by investigating whether polymorphisms within the ORAI1 gene are associated with incidence of heart and vascular diseases in adults. We performed a candidate gene association analysis of the genetic alterations of ORAI1 and their potential association with the risk of CVD and related metabolic diseases in UK Biobank participants from White British background.…”