Sensitivity of opioid receptor-like receptor ORL1 for chemical modification on nociceptin, a naturally occurring nociceptive peptide

Yasuyuki Shimohigashi, Ryo Hatano, Tsugumi Fujita, Rie Nakashima, Takeru Nose, Tetsujo Sujaku, Aki Saigo, Katsuhiro Shinjo, Atsushi Nagahisa

Research output: Contribution to journalArticle

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Abstract

Nociceptin or orphanin FQ is a novel neuropeptide that activates an opioid-like G protein-coupled receptor ORL1. This heptadecapeptide FGGFTGARKSARKLANQ resembles κ-opioid peptide dynorphin A but exhibits an opposite effect to make animals hyperreactive to nociceptive stimulations (Meunier, J.-C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.-L., Guillemot, J.-C., Ferrara, P., Monsarrat, B., Mazarguil, H., Vassart, G., Parmentier, M., and Costentin, J. (1995) Nature 377, 532-535; Reinscheid, R. K., Nothacker, H.-P., Bourson, A., Ardati, A., Henningsen, R. A., Bunzow, J. R., Grandy, D. K., Langen, H., Monsma, F. J., Jr., and Civelli, O. (1995) Science 270, 792-794). In the present study, it was found that guinea pig brain contains receptors to which nociceptin binds much more strongly than to ORL1 receptors expressed in human 293 cells. Although the Tyr1 → Phe substitution for dynorphin A eliminates almost completely an ability to bind to opioid receptors, the Phe1 → Tyr substitution in nociceptin was found to retain almost fully both receptor binding affinity and in vivo hyperalgesic activity in tail-flick assay. Nociceptin was extremely weak to bind to opioid receptors, while Tyr1- nociceptin exhibited 10-40 times increased affinity, especially for μ receptors, due to its N-terminal sequential identity to opioid peptides. Shortened analogs of dynorphin A are known to retain receptor binding ability and analgesic activity, whereas the removal of C-terminal hexa- or decapeptide from nociceptin totally abolished the affinity for the ORL1 receptor. These results indicated that the mode of interaction between nociceptin and ORL1 receptor is quite different from that between dynorphin and opioid receptor and that the C-terminal portion of nociceptin is crucial for receptor recognition.

Original languageEnglish
Pages (from-to)23642-23645
Number of pages4
JournalJournal of Biological Chemistry
Volume271
Issue number39
DOIs
Publication statusPublished - Oct 10 1996

Fingerprint

Chemical modification
Opioid Receptors
Peptides
Dynorphins
Opioid Peptides
Substitution reactions
G-Protein-Coupled Receptors
nociceptin
nociceptin receptor
Neuropeptides
Opioid Analgesics
Analgesics
Tail
Guinea Pigs
Assays
Brain
Animals

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Sensitivity of opioid receptor-like receptor ORL1 for chemical modification on nociceptin, a naturally occurring nociceptive peptide. / Shimohigashi, Yasuyuki; Hatano, Ryo; Fujita, Tsugumi; Nakashima, Rie; Nose, Takeru; Sujaku, Tetsujo; Saigo, Aki; Shinjo, Katsuhiro; Nagahisa, Atsushi.

In: Journal of Biological Chemistry, Vol. 271, No. 39, 10.10.1996, p. 23642-23645.

Research output: Contribution to journalArticle

Shimohigashi, Y, Hatano, R, Fujita, T, Nakashima, R, Nose, T, Sujaku, T, Saigo, A, Shinjo, K & Nagahisa, A 1996, 'Sensitivity of opioid receptor-like receptor ORL1 for chemical modification on nociceptin, a naturally occurring nociceptive peptide', Journal of Biological Chemistry, vol. 271, no. 39, pp. 23642-23645. https://doi.org/10.1074/jbc.271.39.23642
Shimohigashi, Yasuyuki ; Hatano, Ryo ; Fujita, Tsugumi ; Nakashima, Rie ; Nose, Takeru ; Sujaku, Tetsujo ; Saigo, Aki ; Shinjo, Katsuhiro ; Nagahisa, Atsushi. / Sensitivity of opioid receptor-like receptor ORL1 for chemical modification on nociceptin, a naturally occurring nociceptive peptide. In: Journal of Biological Chemistry. 1996 ; Vol. 271, No. 39. pp. 23642-23645.
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abstract = "Nociceptin or orphanin FQ is a novel neuropeptide that activates an opioid-like G protein-coupled receptor ORL1. This heptadecapeptide FGGFTGARKSARKLANQ resembles κ-opioid peptide dynorphin A but exhibits an opposite effect to make animals hyperreactive to nociceptive stimulations (Meunier, J.-C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.-L., Guillemot, J.-C., Ferrara, P., Monsarrat, B., Mazarguil, H., Vassart, G., Parmentier, M., and Costentin, J. (1995) Nature 377, 532-535; Reinscheid, R. K., Nothacker, H.-P., Bourson, A., Ardati, A., Henningsen, R. A., Bunzow, J. R., Grandy, D. K., Langen, H., Monsma, F. J., Jr., and Civelli, O. (1995) Science 270, 792-794). In the present study, it was found that guinea pig brain contains receptors to which nociceptin binds much more strongly than to ORL1 receptors expressed in human 293 cells. Although the Tyr1 → Phe substitution for dynorphin A eliminates almost completely an ability to bind to opioid receptors, the Phe1 → Tyr substitution in nociceptin was found to retain almost fully both receptor binding affinity and in vivo hyperalgesic activity in tail-flick assay. Nociceptin was extremely weak to bind to opioid receptors, while Tyr1- nociceptin exhibited 10-40 times increased affinity, especially for μ receptors, due to its N-terminal sequential identity to opioid peptides. Shortened analogs of dynorphin A are known to retain receptor binding ability and analgesic activity, whereas the removal of C-terminal hexa- or decapeptide from nociceptin totally abolished the affinity for the ORL1 receptor. These results indicated that the mode of interaction between nociceptin and ORL1 receptor is quite different from that between dynorphin and opioid receptor and that the C-terminal portion of nociceptin is crucial for receptor recognition.",
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