STIM1 and Orai1 regulate Ca²⁺ microdomains for activation of transcription

Since calcium (Ca²⁺) regulates a large variety of cellular signaling processes in a cell's life, precise control of Ca²⁺ concentrations within the cell is essential. This enables the transduction of information via Ca²⁺ changes in a time-dependent and spatially defined manner. Here, we review molecular and functional aspects of how the store-operated Ca²⁺ channel Orai1 creates spatiotemporal Ca²⁺ microdomains. The architecture of this channel is unique, with a long helical pore and a six-fold symmetry. Energetic barriers within the Ca²⁺ channel pathway limit permeation to allow an extensive local Ca²⁺ increase in close proximity to the channel. The precise timing of the Orai1 channel function is controlled by direct binding to STIM proteins upon Ca²⁺ depletion in the endoplasmic reticulum. These induced Ca²⁺ 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.