ReviewPore opening mechanism of CRAC channels

- Store-operated calcium entry regulates many functions including immunity, muscle contraction, and vasculature function.
- Two hydrophobic residues in the pore, V102 and F99, control the gating of CRAC channels.
- V102 and F99 function as a gate by presenting a free energy barrier for water and ions in the pore.
- A modest rotation of the pore helix moves F99 away from the pore axis to initiate channel opening.

Three decades ago, James W. Putney Jr. conceptualized the idea of store-operated calcium entry (SOCE) to explain how depletion of endoplasmic reticulum (ER) Ca2+ stores evokes Ca2+ influx across the plasma membrane. Since the publication of this highly influential idea, it is now established that SOCE is universal among non-excitable and probably even many types of excitable cells, and contributes to numerous effector functions impacting immunity, muscle contraction, and brain function. The molecules encoding SOCE, the STIM and Orai proteins, are now known and our understanding of how this pathway is activated in response to ER Ca2+ store depletion has advanced significantly. In this review, we summarize the current knowledge of how Orai1 channels are activated by STIM1, focusing on recent work supporting a hydrophobic gating mechanism for the opening of the Orai1 channel pore.

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