The STIM-Orai Pathway: The Interactions Between STIM and Orai

A primary Ca²⁺ entry pathway in non-excitable cells is established by the Ca²⁺ release-activated Ca²⁺ channels. Their two limiting molecular components include the Ca²⁺-sensor protein STIM1 located in the endoplasmic reticulum and the Orai channel in the plasma membrane. STIM1 senses the luminal Ca²⁺ content, and store depletion induces its oligomerization into puncta-like structures, thereby triggering coupling to as well as activation of Orai channels. A C-terminal STIM1 domain is assumed to couple to both C- and N-terminal, cytosolic strands of Orai, accomplishing gating of the channel. Here we highlight the inter- and intramolecular steps of the STIM1-Orai signaling cascade together with critical sites of the pore structure that accomplishes Ca²⁺ permeation.