Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Neuroscience volume 7, pages 118–125 (2004)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Nociceptin inhibition of DRG calcium currents.
Figure 2: Nociceptin inhibition of cloned calcium channels.
Figure 3: ORL1 modulation of N-type calcium channels in the presence and absence of nociceptin is dependent on receptor expression.
Figure 4: Biochemical interactions between ORL1 receptors or N-type channels.
Figure 5: Determinants of ORL1 receptor modulation of N-type calcium channels expressed in tsA-201 cells.
Figure 6: Agonist-independent inhibition of native non-L-type channels of acutely dissociated DRG neurons.

Similar content being viewed by others

References

  1. Beedle, A.M. & Zamponi, G.W. Modulation of high voltage–activated calcium channels by G protein–coupled receptors. in Calcium Channel Pharmacology (ed., McDonough, S.) (Kluwer Academic/Plenum Publishing, New York, 2003).

    Google Scholar 

  2. Bunzow, J.R. et al. Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type. FEBS Lett. 347, 284–288 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Bertorelli, R. et al. Nociceptin and the ORL-1 ligand [Phe1psi (CH2-NH)Gly2]nociceptin(1-13)NH2 exert anti-opioid effects in the Freund's adjuvant-induced arthritic rat model of chronic pain. Br. J. Pharmacol. 128, 1252–1258 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ahmadi, S., Liebel, J.T. & Zeilhofer, H.U. The role of the ORL1 receptor in the modulation of spinal neurotransmission by nociceptin/orphanin FQ and nocistatin. Eur. J. Pharmacol. 412, 39–44 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Mollereau, C., Moisand, C., Butour, J.L., Parmentier, M. & Meunier, J.C. Replacement of Gln280 by His in TM6 of the human ORL1 receptor increases affinity but reduces intrinsic activity of opioids. FEBS Lett. 395, 17–21 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Xu, X., Hao, J.W. & Wiesenfeld-Hallin, Z. Nociceptin of antinociceptin: potent spinal antinociceptive effect of orphanin FQ/nociceptin in the rat. Neuroreport 7, 2092–2094 (1996).

    CAS  PubMed  Google Scholar 

  7. Knoflach, F., Reinscheid, R.K., Civelli, O. & Kemp, J.A. Modulation of voltage-gated calcium channels by orphanin FQ in freshly dissociated hippocampal neurons. J. Neurosci. 16, 6657–6664 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Connor, M. & Christie, M.J. Modulation of Ca2+ channel currents of acutely dissociated rat periaqueductal grey neurons. J. Physiol. 15, 47–58 (1998).

    Article  Google Scholar 

  9. Larsson, K.P., Olsen, U.B. & Hansen, A.J. Nociceptin is a potent inhibitor of N-type Ca2+ channels in rat sympathetic ganglion neurons. Neurosci. Lett. 296, 121–124 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Morikawa, H. et al. Nociceptin receptor-mediated Ca2+ channel inhibition and its desensitization in NG108-15 cells. Eur. J. Pharmacol. 351, 247–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Abdulla, F.A. & Smith, P.A. Nociceptin inhibits T-type Ca2+ channel current in rat sensory neurons by a G-protein-independent mechanism. J. Neurosci. 17, 8721–8728 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Borgland, S.L., Connor, M. & Christie, M.J. Nociceptin inhibits calcium channel currents in a subpopulation of small nociceptive trigeminal ganglion neurons in mouse. J. Physiol. 536, 35–47 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zamponi, G.W. Determinants of G protein inhibition of presynaptic calcium channels. Cell. Biochem. Biophys. 34, 79–94 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Koch, W.J., Hawes, B.E., Inglese, J., Luttrell, L.M. & Lefkowitz, R.J. Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G beta gamma-mediated signalling. J. Biol. Chem. 269, 6193–6197 (1994).

    CAS  PubMed  Google Scholar 

  15. Albert, P.R., Morris, S.J., Ghahremani, M.H., Storring, J.M. & Lembo, P.M. A putative alpha-helical G beta gamma-coupling domain in the second intracellular loop of the 5-HT1A receptor. Ann. NY Acad. Sci. 861, 146–161 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Lembo, P.M., Ghahremani, M.H., Morris, S.J. & Albert, P.R. A conserved threonine residue in the second intracellular loop of the 5–hydroxytryptamine 1A receptor directs signalling specificity. Mol. Pharmacol. 52, 164–171 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Wu, X., Kushwaha, N., Albert, P.R. & Penington, N.J. A critical protein kinase C phosphorylation site on the 5-HT(1A) receptor controlling coupling to N-type calcium channels. J. Physiol. 538, 41–51 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arnot, M.I., Stotz, S.C., Jarvis, S.E. & Zamponi, G.W. Differential modulation of N-type 1B and P/Q-type 1A calcium channels by different G protein subunit isoforms. J. Physiol. 527, 203–212 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Beech, D.J., Bernheim, L. & Hille, B. Pertussis toxin and voltage dependence distinguish multiple pathways modulating calcium channels of rat sympthetic neurons. Neuron 8, 90–106 (1992).

    Article  Google Scholar 

  20. Luebke, J.I. & Dunlap, K.I. Sensory neuron N-type calcium currents are inhibited by both voltage-dependent and -independent mechnaisms. Pflugers Arch. 428, 499–507 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Kammermeier, P.J., Ruiz-Valesco, V. & Ikeda, S.R. A voltage-independent calcium current inhibitory pathway activated by muscarinic agonists in rat sympathetic neurons requires both Gαq/11 and Gβγ. J. Neurosci. 20, 5623–5629 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schiff, M.L. et al. Tyrsoine-kinase-dependent recruitment of RGS12 to the N-type calcium channel. Nature 408, 723–727 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Diverse-Pieluissi, M., Goldsmith, P.K. & Dunlap, K. Transmitter-mediated inhibition of N-type calcium channels in sensory neurons involves multiple GTP-binding proteins and subunits. Neuron 14, 191–200 (1995).

    Article  Google Scholar 

  24. De Waard, M. et al. Direct binding of G-protein betagamma complex to voltage-dependent calcium channels. Nature 385, 446–450 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Herlitze, S. et al. Modulation of Ca2+ channels by G protein βγ subunits. Nature 380, 258–262 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Ikeda, S.R. Voltage-dependent modulation of N-type calcium channels by G-protein βγ subunits. Nature 380, 255–258 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Zamponi, G.W., Bourinet, E., Nelson, D., Nargeot, J. & Snutch, T.P. Crosstalk between G proteins and protein kinase C mediated by the calcium channel alpha1 subunit. Nature 385, 442–446 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Seifert, R. & Wenzel-Seifert, K. Constitutive activity of G protein-coupled receptors: cause of disease and common property of wild-type receptors. Nauyn Schmiedebergs Arch. Pharmacol. 366, 381–416 (2002).

    Article  CAS  Google Scholar 

  29. Davare, M.A. et al. A beta2 adrenergic receptor signalling complex assembled with the Ca2+ channel Cav1.2. Science 293, 98–101 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Lavine, N. et al. G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase. J. Biol. Chem. 277, 46010–46019 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Emmerson, P.J. & Miller, R.J. Pre- and postsynaptic actions of opioid and orphan opioid agonists in the rat arcuate nucleus and ventromedial hypothalamus in vitro. J. Physiol. 517, 431–445 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Meis, S. & Pape, H.C. Control of glutamate and GABA release by nociceptin/orphanin FQ in the rat lateral amygdala. J. Physiol. 532, 701–712 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tallent, M.K., Madamba, S.G. & Siggins, G.R. Nociceptin reduces epileptiform events in CA3 hippocampus via presynaptic and postsynaptic mechanisms. J. Neurosci. 21, 6940–6948 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Venkatesan, P., Wang, J., Evans, C., Irnaten, M. & Mendelowitz, D. Nociceptin inhibits gamma-aminobutyric acidergic inputs to cardiac parasympathetic neurons in the nucleus ambiguus. J. Pharmacol. Exp. Ther. 300, 78–82 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Monteillet-Agius, G., Fein, J., Anton, B. & Evans, C.J. ORL-1 and mu opioid receptor antisera label different fibers in areas involved in pain processing. J. Comp. Neurol. 399, 373–383 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Neal, C.R. et al. Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat. J. Comp. Neurol. 406, 503–547 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Wick, M.J. et al. Isolation of a novel cDNA encoding a putative membrane receptor with high homology to the cloned mu, delta, and kappa opioid receptors. Brain Res. Mol. Brain Res. 27, 37–44 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Manabe, T. et al. Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors. Nature 394, 577–581 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Briscini, L., Corradini, L., Ongini, E. & Bertorelli, R. Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury. Eur. J. Pharmacol. 447, 59–65 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Gouarderes, C., Tafani, J.A., Meunier, J., Jhamandas, K. & Zajac, J. Nociceptin receptors in the rat spinal cord during morphine tolerance. Brain Res. 838, 85–94 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Jia, Y., Linden, D.R., Serie, J.R. & Seybold, V.S. Nociceptin/orphanin FQ binding increases in superficial laminae of the rat spinal cord during persistent peripheral inflammation. Neurosci. Lett. 250, 21–24 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Kest, B. et al. Morphine tolerance and dependence in nociceptin/orphanin FQ transgenic knock-out mice. Neurosci. 104, 217–222 (2001).

    Article  CAS  Google Scholar 

  43. Ueda, H., Inoue, M., Takeshima, H. & Iwasawa, Y. Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J. Neurosci. 20, 7640–7647 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Latour, I., Hamid, J., Beedle, A.M., Zamponi, G.W. & Macvicar, B.A. Expression of voltage-gated Ca2+ channel subtypes in cultured astrocytes. Glia 41, 347–353 (2003).

    Article  PubMed  Google Scholar 

  45. Beedle, A.M., Hamid, J. & Zamponi, G.W. Inhibition of transiently expressed low- and high-voltage-activated calcium channels by trivalent metal cations. J. Membr. Biol. 187, 225–238 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Monteil, A. et al. Specific properties of T-type calcium channels generated by the human alpha 1I subunit. J. Biol. Chem. 275, 16530–16535 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Magga, J.M., Jarvis, S.E., Arnot, M.I., Zamponi, G.W. & Braun, J.E. Cysteine string protein regulates G protein modulation of N-type calcium channels. Neuron 28, 195–204 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Jarvis, S.E., Magga, J.M., Beedle, A.M., Braun, J.E. & Zamponi, G.W. G protein modulation of N-type calcium channels is facilitated by physical interactions between syntaxin 1A and Gbetagamma. J. Biol. Chem. 275, 6388–6394 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Ouardouz, M. et al. Depolarization-induced Ca2+ release in ischemic spinal cord white matter involves L-type Ca2+ channel activation of ryanodine receptors. Neuron 40, 56–63 (2003).

    Article  Google Scholar 

  50. Kaneko, S. et al. Identification and characterization of novel human Cav2.2 (alpha1B) calcium channel variants lacking the synaptic protein interaction site. J. Neurosci. 22, 82–92 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by an operating grant to G.W.Z. from the Canadian Institutes of Health Research (CIHR). G.W.Z. is a CIHR Investigator and an Alberta Heritage Foundation for Medical Research (AHFMR) senior scholar. A.M.B. held studentship awards from AHFMR and the Natural Sciences and Engineering Research Council. C.J.D. is the recipient of an AHFMR studentship, C.A. holds postdoctoral fellowships from the AHFMR and the Heart and Stroke Foundation of Canada. E.B. is supported by the IUD foundation and the PICS program of the CNRS.

Author information

Authors and Affiliations

  1. Department of Physiology & Biophysics, Cellular and Molecular Neurobiology Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Alberta, Canada

    Aaron M Beedle, John E McRory, Clinton J Doering, Christophe Altier, Jawed Hamid & Gerald W Zamponi

  2. Département de Physiologie, LGF CNRS UPR2580, Montpellier, 34396, France

    Olivier Poirot, Christian Barrere, Joel Nargeot & Emmanuel Bourinet

Authors
  1. Aaron M Beedle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John E McRory
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olivier Poirot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Clinton J Doering
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christophe Altier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christian Barrere
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jawed Hamid
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joel Nargeot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Emmanuel Bourinet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gerald W Zamponi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald W Zamponi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beedle, A., McRory, J., Poirot, O. et al. Agonist-independent modulation of N-type calcium channels by ORL1 receptors. Nat Neurosci 7, 118–125 (2004). https://doi.org/10.1038/nn1180

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1180

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing