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

J Theor Biol. 2019 Jun 7:470:64-75. doi: 10.1016/j.jtbi.2019.02.010. Epub 2019 Mar 7.

Abstract

Release of Ca2+ from endoplasmatic retriculum (ER) Ca2+ stores causes stromal interaction molecules (STIM) in the ER membrane and ORAI proteins in the plasma membrane (PM) to interact and form the Ca2+ release activated Ca2+ (CRAC) channels, which represent a major Ca2+ 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 Ca2+ influx into the cell. On the basis of the model of Hoover and Lewis (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.

Keywords: CRAC channel; ORAI1; ROS; Reaction-diffusion model; STIM1; Stoichiometry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling*
  • Humans
  • Models, Biological*
  • Mutation*
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / metabolism
  • ORAI1 Protein* / genetics
  • ORAI1 Protein* / metabolism
  • Reactive Oxygen Species / metabolism*
  • Stromal Interaction Molecule 1* / genetics
  • Stromal Interaction Molecule 1* / metabolism

Substances

  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • Reactive Oxygen Species
  • STIM1 protein, human
  • Stromal Interaction Molecule 1