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Related Experiment Videos

Store-Operated Calcium Channels: From Function to Structure and Back Again.

Richard S Lewis1

  • 1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305.

Cold Spring Harbor Perspectives in Biology
|October 2, 2019
PubMed
Summary

Store-operated calcium entry (SOCE) channels, like CRAC channels, are activated by endoplasmic reticulum (ER) calcium depletion. STIM proteins sense ER calcium loss and activate Orai proteins to control calcium influx.

Related Experiment Videos

Area of Science:

  • Cell Biology
  • Ion Channel Physiology
  • Molecular Biophysics

Background:

  • Store-operated calcium entry (SOCE) is a critical process mediated by ion channels activated upon endoplasmic reticulum (ER) calcium depletion.
  • The calcium release-activated calcium (CRAC) channel is a well-characterized SOCE channel with vital physiological roles and implications in various pathologies.
  • CRAC channels assemble at ER-plasma membrane (PM) junctions via interactions between STIM and Orai proteins.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying CRAC channel activation and function.
  • To investigate the structural and functional interplay between STIM and Orai proteins.
  • To understand the role of ER-PM junction architecture in calcium and lipid transport.

Main Methods:

  • Cell biology techniques to study ER-PM junction architecture and protein interactions.
  • Molecular mutagenesis and electrophysiology to probe STIM-Orai interactions and channel gating.
  • Structural biology approaches to determine the architecture of STIM and Orai proteins.

Main Results:

  • STIM proteins, sensing ER calcium depletion, bind and activate Orai proteins at ER-PM junctions to form CRAC channels.
  • Structural studies reveal insights into STIM's activation states and Orai binding.
  • STIM-binding stoichiometry is crucial for CRAC channel opening, high calcium selectivity, and low conductance.

Conclusions:

  • CRAC channel function is tightly regulated by the dynamic interaction between STIM and Orai proteins at specialized ER-PM junctions.
  • Understanding STIM-Orai mechanisms provides insights into calcium signaling and potential therapeutic targets for diseases linked to SOCE dysregulation.