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Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai/TRPC model for

Yanhong Liao1, Christian Erxleben, Joel Abramowitz

  • 1Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 22, 2008
PubMed

Insights

Store-operated Ca(2+) entry (SOCE) channels likely involve both Orai and TRPC proteins, not just Orai alone. This finding clarifies the molecular composition of crucial calcium channels essential for cell function.

Area of Science:

  • Cell Biology
  • Molecular Physiology
  • Ion Channel Function

Background:

  • Receptor-operated Ca(2+) entry (ROCE) and store-operated Ca(2+) entry (SOCE) are vital cellular functions.
  • Impairment of these calcium entry pathways can be life-threatening.
  • The precise molecular composition of channels mediating ROCE and SOCE remains largely unknown.

Purpose of the Study:

  • To investigate the molecular components of SOCE and ROCE channels.
  • To determine if TRPC proteins are involved in SOCE, alongside Orai proteins.
  • To elucidate the functional interaction between ROCE and SOCE pathway components.

Main Methods:

  • Reconstitution of Icrac (electrophysiological correlate of SOCE) via Orai1 expression.
  • Utilizing a mutant R91W-Orai1 to inhibit SOCE and ROCE.
  • Co-expression of Orai1 and STIM1 to assess functional calcium entry.

Main Results:

  • TRPC proteins are essential for the reconstitution of Icrac.
  • The R91W-Orai1 mutant effectively inhibits both SOCE and ROCE.
  • Co-expression of Orai1 and STIM1 resulted in functional, gadolinium-resistant ROCE.
  • Demonstrated functional interaction between ROCE and SOCE components.

Conclusions:

  • SOCE/Icrac channels are likely heteromeric complexes comprising both TRPC and Orai proteins.
  • These findings challenge the hypothesis that SOCE channels are formed solely by Orai proteins.
  • The study reveals a functional interplay between ROCE and SOCE pathways, mediated by shared molecular components.

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