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Store-Operated Calcium Channels.

Murali Prakriya1, Richard S Lewis1

  • 1Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California.

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Store-operated calcium channels (SOCs) facilitate calcium signaling by coupling endoplasmic reticulum (ER) calcium depletion to plasma membrane channel activation. STIM and Orai proteins mediate this crucial store-operated calcium entry (SOCE) pathway.

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Area of Science:

  • Cell Biology
  • Molecular Physiology
  • Biochemistry

Background:

  • Store-operated calcium channels (SOCs) are critical for calcium signaling in metazoan cells.
  • Their activation is triggered by calcium (Ca2+) depletion from the endoplasmic reticulum (ER).
  • SOCs regulate diverse cellular functions including gene expression, motility, secretion, development, and immune responses.

Purpose of the Study:

  • To review experimental advances in understanding store-operated calcium entry (SOCE).
  • To elucidate the molecular mechanisms of STIM and Orai protein function in SOCE.
  • To discuss the modulation, inhibition, and physiological/pathological roles of SOCE.

Main Methods:

  • Electrophysiology for initial SOC characterization.
  • Identification and study of STIM (ER Ca2+ sensors) and Orai (channel proteins).
  • Mutagenesis studies and structural insights into STIM-Orai interactions.
  • Analysis of pharmacological inhibitors of SOCE.

Main Results:

  • STIM proteins act as ER Ca2+ sensors, translocating to ER-plasma membrane junctions upon Ca2+ depletion.
  • STIM proteins trap and activate Orai proteins, facilitating store-operated calcium entry (SOCE).
  • Recent structural and mutagenesis data reveal molecular details of STIM-Orai activation and channel gating.

Conclusions:

  • The STIM-Orai axis provides a detailed molecular mechanism for coupling ER Ca2+ levels to plasma membrane calcium influx.
  • Understanding SOCE is crucial for comprehending cellular calcium homeostasis and its role in health and disease.
  • Further research into STIM and Orai modulation and inhibition holds therapeutic potential.