CRAC Channel

CRAC Channel

The calcium release-activated channels (CRAC) channel is a highly Ca2+-selective store-operated channel expressed in T cells, mast cells, and various other tissues. CRAC channels regulate critical cellular processes such as gene expression, motility, and the secretion of inflammatory mediators.

The calcium release-activated calcium (CRAC) channel is a specialized plasma membrane calcium ion channel located on the non-excitatory cytoplasmic membrane and a major pathway for extracellular Ca2+ entry into cells in non-excitatory cells (especially for T lymphocytes and HEK 293 cells).

The composition and the activation of CRAC channels are closely related to two proteins including STIM1 and Orai1. STIM1 is a receptor for the Ca2+ concentration of the endoplasmic reticulum. It senses the concentration of calcium ion in the Ca2+ pool, and then passes the information to the CRAC channel, thereby regulating the opening and closing of the channel. The Orai1 protein is the channel protein required to form the CRAC channel and is a protein that crosses the plasma membrane of the cell. Orai1 is the major subunit protein of the CRAC channel. Each CRAC channel consists of several Orai1 proteins, probably Orai1 and its heteromultimer Orai2 and/or Orai3.

When the endoplasmic reticulum is filled with Ca2+, the Orai1 protein is released as a monomer on the plasma membrane. The EF-hand on the STIM1 dimer binds to Ca2+, and STIM1 cannot interact with the CRAC channel. The CRAC channel is closed. When the cells are stimulated, the concentration of IP3 in the cytoplasm increases, causing a slight increase in intracellular Ca2+ concentration, which further induces the opening of more IP3R channels. A large amount of Ca2+ is released from the endoplasmic reticulum into the cytoplasm. Decreased Ca2+ concentration in the endoplasmic reticulum leads to the EF-hand on the STIM1 dimer to lose Ca2+ and activate STIM1. At the same time, Orai1 protein on the plasma membrane spontaneously assembles into a tetrameric CRAC channel, and active STIM1 dimers activate CRAC channels, allowing extracellular Ca2+ to enter the cell. The PMCA pump and the SERCA pump remove excess Ca2+ from the cytoplasm and also achieve backfilling of Ca2+.

Aberrant CRAC channel activity can transform into human disorders, such as SCID disorders, autoimmunity, allergy and polyposis, inflammatory bowel disease and certain cancers. Aberrant mast-cell activation is linked to a range of allergic disorders including asthma, rhinitis, eczema and nasal polyposis. CRAC channels can be a novel potential target for drugs aimed at managing asthma. The pyrazole derivative BTP2 blocks CRAC channels and thus blockssubsequent interleukin secretion in T cells97, and histamine release and leukotriene production in mast cells98. Another disorder in which CRAC channels is an effective therapeutic target is inflammatory bowel disease, in which T cells are thought to play a prominent pathophysiological role. CRAC channels have also been implicated in prostate cancer, the second leading cause of neoplastic death in men. It is found that increasing the activity of CRAC channels or increasing the driving force for Ca2+ entry by opening K+ channels could be a new way to promote apoptosis and thus reduce proliferation in prostate cancer.

Some agents are available to block CRAC channels and might serve as useful templates for the synthesis of more selective drugs. The first CRAC channel blockers that was used experimentally was the imidazole antimycotic SKF96365. Although this compound blocked agonist-dependent and store-dependent Ca2+ entry in many cell types, its use was undermined by the finding that it blocked other ion channels with similar potencies. Similar problems happened to econazole, another agent used initially to block CRAC channels. 2-Aminoethyldiphenyl borate (2-APB) is another popular CRAC channel inhibitor although it is plagued by a multitude of off-target actions. 3,5-trifluoromethyl pyrazole derivatives (BTPs) have gain much attention and are first introduced as potent immunosuppressive agents in vitro. They can inhibit cytokine release in human whole blood as well as proliferation of human and rat peripheral blood mononuclear cells. Diethylstilbestrol, a synthetic oestrogen agonist, blocks CRAC channels in mast cells and store-operated cation channels in vascular smooth muscle, as well as in rat microglia. Carboxyamidotriazole was initially reported to be an inhibitor of store-operated Ca2+ entry in non-excitable cells. It can inhibit angio-genesis, tumour growth, invasion and metastasis, and has been tested in patients with solid tumours in Phase I and Phase II clinical trials. Synta compound 66 is a new inhibitor with structural similarities to BTP2. It is reported that it could suppresse the release of several interleukins as well as interferon-γ in biopsy samples taken from inflamed areas of patients with inflammatory bowel disease.

As abnormal CRAC channel activity has been linked to a growing number of diseases, CRAC channel inhibitors could therefore be of considerable clinical benefit and biomedical research. BOC Sciences can provide many CRAC channel blockers with high quality for you. BOC Sciences is equipped with advanced equipment and professional staffs are available for your service. For more detailed information and more customized solution, please do not hesitate to contact us. We are at your service all the time.

Reference:

Anant, B. P., (2010) Store-operated CRAC channels: function in health and disease. Nature Reviews Drug Discovery, 9: 399-410.

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