Understanding the regulation of STIM1-ORAI1 interaction using a reaction-diffusion model

Release of Ca 2+ from endoplasmatic retriculum (ER) Ca 2+ stores causes stromal interaction molecules (STIM) in the ER membrane and ORAI proteins in the plasma membrane (PM) to interact and form the Ca 2+ release activated Ca 2+ (CRAC) channels, which represent a major Ca 2+ entry route in non-excitable cells and thus control various cell functions. Extracellular reactive oxygen species (ROS) can modulate the CRAC current I crac via oxidation of ORAI1. We formulate a reaction-diffusion model to quantify the STIM1-ORAI1 interaction during CRAC channel formation and analyze different ORAI1 channel stoichiometries and different ratios of STIM1 and ORAI1 in comparison with experimental data. We incorporate the inhibition of ORAI1 channels by ROS into our model and calculate its contribution to the CRAC channel amplitude. We find that the possibility of reactions between CRAC channel subunits and established CRAC channels tunes the total amount of Ca 2+ influx and determines which CRAC channel configuration is mostly preferred. High numbers of ROS-inhibited ORAI1 dimers (in comparison to non-inhibited ORAI1 dimers) are needed to induce a strong decrease of Ca 2+ influx compared to the wildetype (WT) case.