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Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels

Michael T Nelson1, Jiwan Woo, Ho-Won Kang

  • 1Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|August 3, 2007
PubMed

Insights

Reducing agents and metal chelators sensitize pain-sensing neurons by removing zinc ions from T-type calcium channels (Ca(v)3.2), lowering the threshold for neuronal excitability.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pain Research

Background:

  • T-type Ca2+ channels (T-channels) are crucial for regulating the excitability of peripheral pain-sensing neurons (nociceptors).
  • The precise molecular mechanisms governing T-channel function in nociceptors remain largely undefined.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which T-channels modulate nociceptor function.
  • To investigate the role of zinc ions and reducing agents in T-channel activity and nociception.

Main Methods:

  • Utilized in vitro and in vivo models of dorsal root ganglion (DRG) nociceptors.
  • Investigated the effects of reducing agents and metal chelators on Ca(v)3.2 T-channel currents.
  • Examined the interaction of zinc ions with specific extracellular histidine residues on Ca(v)3.2 channels.

Main Results:

  • Reducing agents and endogenous metal chelators sensitize C-type DRG nociceptors.
  • Sensitization occurs via chelation of Zn2+ ions from extracellular histidine residues on Ca(v)3.2 T-channels.
  • This process relieves tonic channel inhibition, enhances Ca(v)3.2 currents, and lowers the threshold for nociceptor activation.

Conclusions:

  • A novel mechanism for nociceptor sensitization involving T-channels and zinc ions has been identified.
  • Zn2+ ions, along with reducing agents, amino acids, and proteins that chelate Zn2+, act as endogenous modulators of Ca(v)3.2 channels and nociceptor excitability.

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