ORAI-mediated calcium entry: Mechanism and roles, diseases and pharmacology

ORAI1 is a protein located on the plasma membrane that acts as a calcium channel. Calcium enters via ORAI1 as a mechanism to refill the sarcoplasmic/endoplasmic reticulum calcium stores, the depletion of which can be detected by the sensor protein STIM1. Isoforms of these proteins ORAI2, ORAI3 and STIM2 also have roles in cellular calcium homeostasis but are less well characterized. This pathway of filling the calcium stores is termed store-operated calcium entry and while the pathway itself was proposed in 1986, the identity of the key molecular components was only discovered in 2005 and 2006. The characterization of the ORAI and STIM proteins has provided clearer information on some calcium-regulated pathways that are important in processes from gene transcription to immune cell function. Recent studies have also suggested the importance of the components of ORAI-mediated calcium entry in some diseases or processes significant in disease including the migration of breast cancer cells and thrombus formation. This review will provide a brief overview of ORAI-mediated calcium entry, its role in physiological and pathophysiological processes, as well as current and potential pharmacological modulators of the components of this important cellular calcium entry pathway.