STIM1 and Orai1 regulate Ca2+ microdomains for activation of transcription

Since calcium (Ca 2+ ) regulates a large variety of cellular signaling processes in a cell's life, precise control of Ca 2+ concentrations within the cell is essential. This enables the transduction of information via Ca 2+ changes in a time-dependent and spatially defined manner. Here, we review molecular and functional aspects of how the store-operated Ca 2+ channel Orai1 creates spatiotemporal Ca 2+ microdomains. The architecture of this channel is unique, with a long helical pore and a six-fold symmetry. Energetic barriers within the Ca 2+ channel pathway limit permeation to allow an extensive local Ca 2+ increase in close proximity to the channel. The precise timing of the Orai1 channel function is controlled by direct binding to STIM proteins upon Ca 2+ depletion in the endoplasmic reticulum. These induced Ca 2+ microdomains are tailored to, and sufficient for, triggering long-term activation processes, such as transcription factor activation and subsequent gene regulation. We describe the principles of spatiotemporal activation of the transcription factor NFAT and compare its signaling characteristics to those of the autophagy regulating transcription factors, MITF and TFEB. • The unique pore structure of the Orai channel favors the formation of Ca 2+ microdomains. • The Orai channel architecture is unique in comparison to other Ca 2+ selective channels. • Isoform specific STIM residues tune physiological functions and spatio-temporal Ca 2+ signals. • The binding site of STIM1 undergoes conformational changes to interact with Orai1. • Precise processing of incoming Ca 2+ signals facilitates multiple transcriptional programs.