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BK Potassium Channels Suppress Cavα2δ Subunit Function to Reduce Inflammatory and Neuropathic Pain

Fang-Xiong Zhang1, Vinicius M Gadotti1, Ivana A Souza1

  • 1Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Cell Reports
|February 22, 2018
PubMed

Insights

Large conductance calcium-activated potassium (BK) channels interact with Cavα2δ subunits, reducing pain signal transmission. Targeting this interaction with BK channel peptides offers a novel strategy for long-lasting pain relief.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Cavα2δ subunits are crucial for cell-surface expression of Cav2 calcium channels.
  • Upregulation of Cavα2δ-1 after nerve injury enhances pain signal transmission.
  • Cav2.2 channels in the spinal dorsal horn are implicated in pain.
  • Large conductance calcium-activated potassium (BK) channels are involved in neuronal excitability.

Purpose of the Study:

  • To investigate the interaction between BK channels and Cavα2δ subunits.
  • To determine the role of this interaction in pain signaling.
  • To explore the therapeutic potential of targeting this interaction for analgesia.

Main Methods:

  • Coexpression of BK channels and Cav2 calcium channels.
  • Biochemical analysis to identify interaction domains.
  • Assessment of cell-surface expression and current density.
  • Intrathecal delivery of virus constructs encoding BK channel peptides in mouse pain models.

Main Results:

  • BK channels interact with Cavα2δ subunits, reducing Cav2 channel cell-surface expression and current density.
  • The extracellular N terminus of the BK channel is critical for this interaction.
  • Intrathecal delivery of a membrane-anchored BK channel N terminus peptide produced long-lasting analgesia in inflammatory and neuropathic pain models.

Conclusions:

  • BK channels act as endogenous ligands for Cavα2δ subunits.
  • This interaction modulates Cav2 channel function and pain transmission.
  • Targeting the BK channel-Cavα2δ interaction presents a promising analgesic strategy.
Keywords:
BK channelallodyniaalpha2-delta subunitcalcium channelgabapentinhyperalgesiapainpregabalin

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