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ORL1 receptor-mediated internalization of N-type calcium channels

Christophe Altier1, Houman Khosravani, Rhian M Evans

  • 1Department of Physiology and Biophysics, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

Nature Neuroscience
|November 29, 2005
PubMed

Insights

Opioid receptor like receptor 1 (ORL1) signaling complexes internalize upon nociceptin exposure, reducing N-type calcium channel activity. This mechanism offers a novel approach for long-term pain pathway regulation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Opioid receptor like receptor 1 (ORL1) and N-type calcium channels form signaling complexes that inhibit nociceptive signal transmission.
  • These complexes mediate tonic inhibition of calcium entry, crucial for pain signaling.

Purpose of the Study:

  • To investigate the effect of prolonged agonist exposure on ORL1-N-type calcium channel signaling complexes.
  • To determine the mechanism and selectivity of agonist-induced internalization and its impact on calcium entry.

Main Methods:

  • Exposure of ORL1 receptors to nociceptin in expression systems and rat dorsal root ganglion neurons.
  • Assessment of protein kinase C activation and internalization of signaling complexes.
  • Measurement of calcium entry and N-type calcium channel localization at the plasma membrane.

Main Results:

  • Prolonged nociceptin exposure induced internalization of ORL1-N-type calcium channel complexes into vesicular compartments.
  • Internalization was dependent on protein kinase C activation and selective for N-type calcium channels.
  • Nociceptin-mediated internalization led to a significant downregulation of calcium entry and selective removal of N-type channels from the plasma membrane.

Conclusions:

  • Nociceptin triggers a protein kinase C-dependent internalization of ORL1-N-type calcium channel complexes.
  • This process selectively downregulates N-type calcium channel activity and calcium entry.
  • This mechanism represents a novel pathway for the long-term regulation of calcium entry in the pain pathway.

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