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Orai1 Boosts SK3 Channel Activation

Adéla Tiffner1, Valentina Hopl1, Romana Schober1,2

  • 1JKU Life Science Center, Institute of Biophysics, Johannes Kepler University Linz, A-4020 Linz, Austria.

Cancers
|December 24, 2021
PubMed

Insights

The calcium-sensitive potassium channel SK3 and the calcium channel Orai1 interact to enhance SK3 currents, a mechanism crucial for cancer cell proliferation. This study reveals how Orai1 modulates SK3 activity, offering insights into cancer progression.

Area of Science:

  • Ion channel biology
  • Molecular cell biology
  • Cancer research

Background:

  • The interaction between SK3 (a Ca2+-sensitive K+ channel) and Orai1 (a Ca2+ channel) is known to increase cytosolic Ca2+ levels, promoting cancer cell proliferation.
  • The precise molecular mechanisms underlying this interplay and its effect on SK3 channel activity have remained unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which Orai1 modulates SK3 channel activity.
  • To investigate the role of STIM1 in the regulation of the SK3-Orai1 interaction.
  • To explore the functional relevance of this interplay in cancer cells.

Main Methods:

  • Heterologous protein expression systems were used to study SK3 and Orai1 interactions.
  • Electrophysiological recordings were performed to measure SK3 K+ currents.
  • Site-directed mutagenesis and co-localization studies were employed to map interaction sites and assess STIM1's role.
  • Experiments were conducted in human prostate cancer cell line LNCaP.

Main Results:

  • Orai1 potentiates SK3 K+ currents, particularly at low cytosolic Ca2+ levels, through close co-localization.
  • Orai1 can restore SK3 channel activity impaired by calmodulin mutants, suggesting interaction at the SK3-CaM binding site.
  • Cytosolic strands and pore residues of Orai1 are critical for functional communication with SK3.
  • STIM1 exhibits a bimodal regulatory role, impeding the SK3-Orai1 interplay under physiological conditions but promoting it upon forced activation.
  • Orai1 dynamically enhances endogenous SK3 channels in LNCaP cells.

Conclusions:

  • Orai1 enhances SK3 channel activity via a positive feedback mechanism, driven by their co-localization and interplay.
  • Specific regions of Orai1 are essential for its functional interaction with SK3.
  • STIM1 dynamically regulates the SK3-Orai1 complex, influencing SK3 currents.
  • The findings provide a molecular basis for the SK3-Orai1 interplay in cancer cell physiology and suggest potential therapeutic targets.
Keywords:
CRAC channelCa2+ activated K+ ion channelsLNCaP cellsOrai1SK channelsSK3STIM1calmodulin

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