Calcium release activated channel

Calcium Release-Activated Channels (CRAC) are specialized plasma membrane Ca²⁺ ion channels. When calcium ions (Ca²⁺) are depleted from the endoplasmic reticulum (a major store of Ca²⁺) of mammalian cells, the CRAC channel is activated to slowly replenish the level of calcium in the endoplasmic reticulum. The plasma membrane protein "Orai" (ORAI1 and ORAI2 in humans) forms the pore of CRAC channel.

Structure

The protein ORAI1 is a structural component of the CRAC calcium channel. ORAI1 interacts with the STIM1 protein. STIM1 is a transmembrane protein of the endoplasmic reticulum (ER). STIM1 can sense the concentration of Ca²⁺ inside the ER. When the concentration of Ca²⁺ inside the ER becomes low, STIM1 proteins aggregate and interact with ORAI1 located in the cell surface membrane.^[1] When concentration of Ca²⁺ inside the ER approaches upper set point, another protein, SARAF (TMEM66) associates with STIM1 to inactivate the store-operated calcium channel (SOCE).^[2]

Function

Changes in the cytoplasmic free Ca²⁺ concentration ([Ca²⁺]c) constitute one of the main pathways by which information is transferred from extracellular signals received by animal cells to intracellular sites. The intracellular Ca²⁺ signal is conveyed by the magnitude, location and duration of the changes in [Ca²⁺]c. Increases in [Ca²⁺]c in a given region of the cytoplasmic space are usually initiated by the binding of an extracellular signaling molecule (agonist) to its plasma-membrane receptors.

Such signals can arise either from the release of stored calcium or the calcium influx across the plasma membrane, but more characteristically, from both routes. A common mechanism by which such cytoplasmic calcium signals are generated involves receptors that are coupled to the activation of phospholipase C. Phospholipase C generates inositol 1,4,5-trisphosphate (IP3), which in turn mediates the discharge of Ca²⁺ from intracellular stores (most commonly components of the endoplasmic reticulum), allowing calcium to be released into the cytosol. In most of the cell, the fall in Ca²⁺ concentration within the lumen of the Ca²⁺-storing organelles subsequently activates plasma membrane Ca²⁺ channels. This calcium influx across the plasma membrane has been called “capacitative calcium entry,” or “store-operated calcium entry”. In non-excitable cells such as blood cells, capacitative calcium entry appears to be the major means of regulated influx of Ca²⁺ and signal transduction. As a second messenger capacitative calcium entry can induce short term cellular responses, such as proteins-protein interactions, granule secretion, etc., but can also initiate longer-term cellular control mechanisms such as genes transcription that support cell growth, apoptosis, differentiation or activation. In in vitro studies, the effect of this necessary calcium signal for activation of genes transcription factor can be induced by the action of calcium ionophores such as ionomycin.

Activation of T lymphocytes is an essential event for the efficient response of the immune system. Disregulation of this phenomenon can lead to immunological disorder such as autoimmune disease or inflammation. This activation requires the involvement of the T cell receptor antigen as well as costimulatory molecules such as CD28. Engagement of this receptor complex will result in a series of signaling cascade, which lead to the production of several cytokines. IL-2 gene transcription, a key event in T cell activation and proliferation, is dependent on the rapid and sustain increase in intracellular Ca²⁺. Targeting the very early events of cascade signaling pathway, by inhibiting the capacitative calcium entry is an efficient way to prevent T cell activation.

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