Reaction-diffusion model for STIM-ORAI interaction: the role of ROS and mutations

TL;DR

This paper develops a reaction-diffusion model to analyze STIM-ORAI interactions during calcium channel formation, incorporating ROS effects and mutations, to better understand calcium influx regulation in cells.

Contribution

The study introduces a reaction-diffusion model based on Hoover and Lewis (2011) to quantify STIM-ORAI interactions, including ROS inhibition and mutation effects, providing new insights into calcium channel dynamics.

Findings

Mutations in ORAI1 significantly reduce CRAC channel amplitude.

ROS inhibits ORAI1 channels, decreasing calcium influx.

Model aligns with experimental data on channel stoichiometry and ratios.

Abstract

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. It is experimentally possible to mutate ORAI1 proteins and therefore modify, especially block, the $Ca^{2+}$ influx into the cell. On the basis of the model of Hoover and Lewis (2011) [Hoover P J and Lewis R S, 2011], 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 observe a large decrease of the CRAC channel amplitude evoked by mutations of ORAI1 proteins.