Calcico | CRAC Channels
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CRAC Channels

CRAC Channels

The calcium ion is a critical second messenger in immune cell types. The distribution and concentration of calcium in these cells encodes modulation of a range of signalling pathways that impact on basic physiological responses such as inflammation, allergic reactions and immune system activation. The CRAC channel has recently emerged as a very promising therapeutic target for disorders characterised by inappropriate immune cell responses. CRAC channel antagonists could offer new options for the many disorders of the immune system.

Ca2+

A rise in cytosolic Ca2+ is a highly conserved signalling mechanism in eukaryotic cells. Cytosolic Ca2+ can increase following release of Ca2+ ions from intracellular Ca2+ stores or after influx through Ca2+-permeable ion channels. Of these processes, store-operated Ca2+ entry (SOCE) is a major mechanism of Ca2+ entry in mammalian cells. It not only refills the stores with Ca2+ but provides trigger Ca2+ for activation of a range of cellular response such as gene expression, cell proliferation, and cytokine release. CRAC channels are the most comprehensively characterised store-operated channels. CRAC channels are exquisitely selective for Ca2+ and have a low unitary conductance. Two proteins make up a functional CRAC channel: the channel pore-forming Orai protein in the plasma membrane, and the calcium sensor stromal interaction molecule (STIM) proteins in the Ca2+ store.

Primary Assay

CRAC channels are present in a variety of immune cells including CD4+ & CD8+ T cells, B cells and mast cells. CRAC antagonists have previously failed in clinical development due to the lack of an appropriate primary assay. To overcome this issue, Calcico have developed a primary assay that allows the selective measure of low-conductance CRAC activity in a high throughput screen format. This enables the identification of selective CRAC antagonists and development of reliable structure-activity profiles.

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