Abstract
Store-operated Ca(2+) entry through Orai1 channels is a primary mechanism for Ca(2+) entry in many cells and mediates numerous cellular effector functions ranging from gene transcription to exocytosis. Orai1 channels are amongst the most Ca(2+) -selective channels known and are activated by direct physical interactions with the endoplasmic reticulum Ca(2+) sensor stromal interaction molecule 1 (STIM1) in response to store depletion triggered by stimulation of a variety of cell surface G-protein coupled and tyrosine kinase receptors. Work in the last decade has revealed that the Orai1 gating process is highly cooperative and strongly allosteric, likely driven by a wave of interdependent conformational changes throughout the protein originating in the peripheral C-terminal ligand binding site and culminating in pore opening. In this review, we survey the structural and molecular features in Orai1 that contribute to channel gating and consider how they give rise to the unique biophysical fingerprint of Orai1 currents.