Article abstract
Nature Neuroscience 7, 118 - 125 (2004)
Published online: 18 January 2004 | doi:10.1038/nn1180
Agonist-independent modulation of N-type calcium channels by ORL1 receptors
Aaron M Beedle1, John E McRory1, Olivier Poirot2, Clinton J Doering1, Christophe Altier1, Christian Barrere2, Jawed Hamid1, Joel Nargeot2, Emmanuel Bourinet2 & Gerald W Zamponi1
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.
- Department of Physiology & Biophysics, Cellular and Molecular Neurobiology Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
- Département de Physiologie, LGF CNRS UPR2580, Montpellier 34396, France.
Correspondence to: Gerald W Zamponi1 e-mail: zamponi@ucalgary.ca
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