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WIREs Membr Transp Signal

IP 3 R function in cells of the immune system

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Calcium ions regulate almost all cellular processes. Inositol 1,4,5‐trisphosphate receptors (IP3Rs) are ubiquitous calcium channels which mediate calcium release primarily from endoplasmic reticulum stores. IP3Rs are activated by the soluble second messenger inositol 1,4,5‐trisphosphate (IP3), which is produced in response to various stimuli by the action of phospholipase C enzymes. Very soon after the discovery that IP3 is a calcium mobilizing second messenger, it was found that T‐cell receptor signaling is dependent upon IP3R activity. It is now known that cell signaling throughout the immune system is dependent upon IP3R‐dependent calcium release for many critical processes, including cellular activation, proliferation, and death. This channel plays a critical role in orchestrating the immune response in health and disease and thus offers potential as a therapeutic target in immune‐related disorders. WIREs Membr Transp Signal 2012,1:329–339. doi: 10.1002/wmts.27

Figure 1.

Calcium‐dependent activation of signaling pathways in T and B lymphocytes. Stimulation of antigen receptors of T and B cells (TCR and BCR) results in recruitment of adaptor and effector molecules leading to activation of phospholipase C (PLC)‐γ. Activated PLC‐γ hydrolyzes phosphatidylinositol 4,5‐bisphosphate into diacylglycerol and Inositol 1,4,5‐trisphosphate (IP3) inducing Inositol 1,4,5‐trisphosphate receptor (IP3R)‐mediated calcium release into cytoplasm from endoplasmic reticulum (ER) stores. Depletion of ER calcium stores causes calcium entry through plasma membrane through the ORAI1 calcium channel in T lymphocytes and ORAI1 and plasma membrane IP3Rs in B lymphocytes. Elevated cytoplasmic calcium levels result in activation of calcium‐dependent signaling proteins, including calmodulin (CaM) and the phosphatase calcineurin. Activated calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), causing its translocation into nucleus and transcriptional activation of NFAT‐dependent promoters.

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Figure 2.

Calcium functions as a critical second messenger regulating T‐cell life and death decisions. Both T‐cell activation and apoptotic signaling pathways are mediated by calcium flux through Inositol 1,4,5‐trisphosphate receptor (IP3R) channels. Engagement of Fas or T‐cell receptors leads to rapid activation of phospholipase C (PLC)‐γ1 and subsequent cytoplasmic calcium flux through IP3R channels initiating distinct signaling pathways. Apoptotic calcium release through IP3R in response to Fas receptor stimulation is positively modulated by the T‐cell receptor (TCR) complex and requires members of canonical TCR pathway, such as tyrosine kinases Lck and Zap70. See text for details.

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TRP/Soc Channels > Store-operated channels (Soc)
Intracellular Channels and Receptors > Inositol-1,4,5 trisphosphate (IP3) Receptors
Receptor Tyrosine Kinases

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