CRAC Channels

Calcium channels in the plasma membrane activated after receptor-mediated calcium release from intracellular stores. Diese channels are present in many cellular types and play pivotal roles in a multitude of cell functions. It was recently shown that Orai proteins are the pore-forming subunit of CRAC channels. They are activated by STIM proteins that sense the Ca2+ content of the endoplasmic reticulum. 

The NHR contains also the conserved Calcineurin docking site, PxlxIT, required for the physical interaction of NEAT and Calcineurin. Dephosphorylation of at least 13 serines residues in the NHR induces a conformational change that exposes the nuclear localization sequences (NLS), allowing the nuclear translocation of NEAT. Rephosphorylation of these residues unmasks the nuclear export sequences that direct transport back to the cytoplasm. Engagement of receptors such as the antigen receptors in T and B cells is coupled to phospholipase C activation and subsequent production of inositol triphosphate. Increased levels of inositol triphosphate lead to the initial release of intracellular stores of calcium. This early increase of calcium induces opening of the plasma membrane calcium-released-activated-calcium (CRAC) channels,... 

Ca2 + transport CRAC channel Cocoa flavanols Apigenin Opuntia ficus indica polyphenols... 

FIGURE 11.2 Formation of puncta structure and redistribution of STIMl. Ca + store depletion leads to a rapid translocation of STIMI into puncta and puncta-formed STIMl migrates from ER sites to the plasma membrane. Thereafter, the CRAC activation domain (CAD) of STIMl directly binds to the N- and C-termini of Orail to open the SOC (CRAC) channel. (From Kurosaki Baba, 2010. Copyright 2010, with permission from Elsevier.)... 

Yonetoku Y, Kubota H, Okamoto Y, Toyosima A, Funatsu M, Ishikawa J, Takeuchi M, Ohta M, Tsukamoto SI (2006) Novel potent and selective caldum-released-activated calcium (CRAC) channel inhibitors. Part 1 synthesis and inhibitory activity of 5-(l-methyl-3-trifluoromethyl-l//-pyrazol-5-yl)-2-thiophenecarboxamides. Bioorg Med Chem 14 4750-4760... 

Chang, W. C. Di Capite, J. et al. (2008). "Local Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels stimulates production of an intracellular messenger and an intercellular pro-inflammatory signal. J Biol Chem, 283(8), 4622-31. 

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