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CRAC Channel
As a universal and remarkably versatile second messenger, cytoplasmic Ca2+ is important in mediating fundamental biological processes including gene expression, cell proliferation, differentiation and apoptosis. There are two major sources contributing to the increase of cytoplasmic Ca2+ concentration, the release of stored Ca2+ within the endoplasmic reticulum (ER) or sarcoplasmic reticulum (SR) and the influx of extracellular Ca2+ across the plasma membrane. The prototypical store-operated Ca2+ channel is the Ca2+ release-activated Ca2+ (CRAC) channel, which is widely distributed and involved in the regulation of a myriad of cellular activities in different cell types, including various subsets of T cells, B cells, mast cells, endothelial cells, platelets, vascular smooth muscle cells and skeletal muscle cells.
CRAC channel is composed of two key components, STIM (STIM1 and STIM2) and ORAI (ORAI1, ORAI2 and ORAI3), with the combination of STIM1/ORAI1 prevails in most cells and thus best characterized. The increase of IP3 concentration induced by activation of PLC activates endoplasmic reticulum (ER)-resident IP3 receptors (IP3R) and causes the release of Ca2+ from ER, which leads to oligomerization and conformational switch of STIM1. The activated STIM1 oligomers then move toward the ER–plasma membrane junctions and trigger Ca2+ influx through direct interaction with an opening of ORAI1 Ca2+ channels in the plasma membrane. Aberrant CRAC channel activity has been noted in several human diseases, including severe combined immunodeficiency (SCID) disorders, allergy, thrombosis, acute pancreatitis, inflammatory bowel disease and cancer, which leads to an increasing interest in developing small molecule compounds that suppress aberrant CRAC channel function.
References
1.Chengsen Tian,et al. Future Med Chem. 2016 May; 8(7): 817–832.
CRAC channel is composed of two key components, STIM (STIM1 and STIM2) and ORAI (ORAI1, ORAI2 and ORAI3), with the combination of STIM1/ORAI1 prevails in most cells and thus best characterized. The increase of IP3 concentration induced by activation of PLC activates endoplasmic reticulum (ER)-resident IP3 receptors (IP3R) and causes the release of Ca2+ from ER, which leads to oligomerization and conformational switch of STIM1. The activated STIM1 oligomers then move toward the ER–plasma membrane junctions and trigger Ca2+ influx through direct interaction with an opening of ORAI1 Ca2+ channels in the plasma membrane. Aberrant CRAC channel activity has been noted in several human diseases, including severe combined immunodeficiency (SCID) disorders, allergy, thrombosis, acute pancreatitis, inflammatory bowel disease and cancer, which leads to an increasing interest in developing small molecule compounds that suppress aberrant CRAC channel function.
References
1.Chengsen Tian,et al. Future Med Chem. 2016 May; 8(7): 817–832.
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