Calcium signaling is important for numerous physiological functions such as lymphocyte activation, muscle contraction, and neuronal transmission. In resting cells, cytosolic calcium concentration is maintained at a very low level by pumps that actively move calcium ions to the extracellular space and to the lumen of endoplasmic reticulum (ER). Following stimulation of many cell surface receptors, calcium is first released from the ER to the cytosol. ER calcium depletion triggers conformational change and oligomerization of the ER membrane protein STIM1, resulting in its translocation to ER-plasma membrane (PM) junctions and activation of the PM calcium channel Orai1. This process is called store-operated calcium entry (SOCE) that brings in calcium from the extracellular space to sustain cytosolic calcium signals, and to refill the ER calcium store following its depletion. Defective SOCE is associated with numerous human diseases, including severe combined immunodeficiency, skeletal myopathy, and neurodegeneration.
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