Abstract
The inhibition of N-type calcium channels by opioid receptor like receptor 1 (ORL1) is a key mechanism for controlling the transmission of nociceptive signals. We recently reported that signaling complexes consisting of ORL1 receptors and N-type channels mediate a tonic inhibition of calcium entry. Here we show that prolonged (∼30 min) exposure of ORL1 receptors to their agonist nociceptin triggers an internalization of these signaling complexes into vesicular compartments. This effect is dependent on protein kinase C activation, occurs selectively for N-type channels and cannot be observed with μ-opioid or angiotensin receptors. In expression systems and in rat dorsal root ganglion neurons, the nociceptin-mediated internalization of the channels is accompanied by a significant downregulation of calcium entry, which parallels the selective removal of N-type calcium channels from the plasma membrane. This may provide a new means for long-term regulation of calcium entry in the pain pathway.
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Acknowledgements
We thank T. Snutch for providing wild-type calcium channel subunits. We thank S. Jarvis for help with HA-Cav2.2 cDNA, and are grateful to J. Hamid, C. Barrere and J. Nargeot for assistance and technical discussions. This work was supported by operating grants to G.W.Z. and S.S.G.F. from the Canadian Institutes of Health Research (CIHR), and grants to E.B. from the Institut UPSA de la Douleur and the Fondation Paul Hamel, and by a CNRS International Programs for Scientific Cooperation (PICS) exchange program. G.W.Z. is a Senior Scholar of the Alberta Heritage Foundation for Medical Research (AHFMR) and a Canada Research Chair in Molecular Neurobiology. S.S.G.F. is also a Canada Research Chair. C.A. holds postdoctoral fellowships from the AHFMR and the Heart and Stroke Foundation of Canada, R.M.E. holds a postdoctoral fellowship from the AHFMR, H.K. holds a Canada Graduate Scholarship and an AHFMR studentship, J.B.P. holds a Foundation for Fighting Blindness studentship, and B.A.V. holds a CIHR Master's studentship.
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Supplementary Fig. 1
Control experiments examining cell type, sizes of nuclei, and distribution of HA-tagged calcium channels. (PDF 430 kb)
Supplementary Fig. 2
Specificity of the ORL1 receptor antibody used in our study. (PDF 327 kb)
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Altier, C., Khosravani, H., Evans, R. et al. ORL1 receptor–mediated internalization of N-type calcium channels. Nat Neurosci 9, 31–40 (2006). https://doi.org/10.1038/nn1605
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DOI: https://doi.org/10.1038/nn1605
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