title: Agonist-independent modulation of N-type calcium channels by ORL1 receptors.
abstract: 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.
authors.affiliation: Department of Physiology & Biophysics, Cellular and Molecular Neurobiology Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Beedle
authors.forename: John E
authors.initials: JE
authors.lastname: McRory
authors.forename: Olivier
authors.initials: O
authors.lastname: Poirot
authors.forename: Clinton J
authors.initials: CJ
authors.lastname: Doering
authors.forename: Christophe
authors.initials: C
authors.lastname: Altier
authors.forename: Christian
authors.initials: C
authors.lastname: Barrere
authors.forename: Jawed
authors.initials: J
authors.lastname: Hamid
authors.forename: Joel
authors.initials: J
authors.lastname: Nargeot
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bourinet
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism; D005727:Ganglia, Spinal / Q000502:physiology; D006801:Humans; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism*; D018847:Opioid Peptides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014665:Vasodilator Agents / Q000494:pharmacology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D020864:Calcium Channels, N-Type; D019204:GTP-Binding Proteins; D018847:Opioid Peptides; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin