Agonist-independent modulation of N-type calcium channels by ORL1 receptors

Nat Neurosci. 2004 Feb;7(2):118-25. doi: 10.1038/nn1180. Epub 2004 Jan 18.


We have investigated modulation of voltage-gated calcium channels by nociceptin (ORL1) receptors. In rat DRG neurons and in tsA-201 cells, nociceptin mediated a pronounced inhibition of N-type calcium channels, whereas other calcium channel subtypes were unaffected. In tsA-201 cells, expression of N-type channels with human ORL1 resulted in a voltage-dependent G-protein inhibition of the channel that occurred in the absence of nociceptin, the ORL1 receptor agonist. Consistent with this observation, native N-type channels of small nociceptive dorsal root ganglion (DRG) neurons also had tonic inhibition by G proteins. Biochemical characterization showed the existence of an N-type calcium channel-ORL1 receptor signaling complex, which efficiently exposes N-type channels to constitutive ORL1 receptor activity. Calcium channel activity is thus regulated by changes in ORL1 receptor expression, which provides a possible molecular mechanism for the development of tolerance to opioid receptor agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium Channels, N-Type / drug effects
  • Calcium Channels, N-Type / metabolism*
  • Cells, Cultured
  • GTP-Binding Proteins / metabolism
  • Ganglia, Spinal / physiology
  • Humans
  • Microscopy, Confocal
  • Neurons / metabolism*
  • Opioid Peptides / pharmacology
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • Vasodilator Agents / pharmacology


  • Calcium Channels, N-Type
  • Opioid Peptides
  • Receptors, Opioid
  • Vasodilator Agents
  • nociceptin
  • nociceptin receptor
  • GTP-Binding Proteins