STIM1 activation of Orai1.

A primary calcium (Ca) entry pathway into non-excitable cells is through the store-operated Ca release activated Ca (CRAC) channel. Ca entry into cells is responsible for the initiation of diverse signalling cascades that affect essential cellular processes like gene regulation, cell growth and death, secretion and gene transcription. Upon depletion of intracellular Ca stores within the endoplasmic reticulum (ER), the CRAC channel opens to refill depleted stores. The two key limiting molecular players of the CRAC channel are the stromal interaction molecule (STIM1) embedded in the ER-membrane and Orai1, residing in the plasma membrane (PM), respectively. Together, they form a highly Ca selective ion channel complex. STIM1 senses the Ca content of the ER and confers Ca store-depletion into the opening of Orai1 channels in the PM for triggering Ca-dependent gene transcription, T-cell activation or mast cell degranulation. The interplay of Orai and STIM proteins in the CRAC channel signalling cascade has been the main focus of research for more than twelve years. This chapter focuses on current knowledge and main experimental advances in the understanding of Orai1 activation by STIM1, thereby portraying key mechanistic steps in the CRAC channel signalling cascade.