Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia

Simple item page
dc.contributor.authorPisanò, Clarissa A.en
dc.contributor.authorMercatelli, Danielaen
dc.contributor.authorMazzocchi, Martinaen
dc.contributor.authorBrugnoli, Albertoen
dc.contributor.authorMorella, Ilariaen
dc.contributor.authorFasano, Stefaniaen
dc.contributor.authorZaveri, Nurulain T.en
dc.contributor.authorBrambilla, Riccardoen
dc.contributor.authorO'Keeffe, Gerard W.en
dc.contributor.authorNeubig, Richard R.en
dc.contributor.authorMorari, Micheleen
dc.contributor.funderUniversità degli Studi di Ferraraen
dc.date.accessioned2024-05-15T10:04:02Z
dc.date.available2024-05-15T10:04:02Z
dc.date.issued2021-11-12en
dc.description.abstractBackground and Purpose: Regulator of G-protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance for l-Dopa-induced dyskinesia. Experimental Approach: HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small-molecule NOP agonist AT-403, using D1-stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with either N/OFQ or AT-403 in the presence of the experimental RGS4 chemical probe, CCG-203920, and D1-stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and l-Dopa to 6-hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. Key Results: RGS4 expression reduced NOFQ and AT-403 potency and efficacy in HEK293T cells. CCG-203920 increased N/OFQ potency in primary rat striatal neurons and potentiated AT-403 response in mouse striatal slices. CCG-203920 enhanced AT-403-mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor-improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by l-Dopa. l-Dopa acutely up-regulated RGS4 in the lesioned striatum. Conclusions and Implications: RGS4 physiologically inhibits NOP receptor signalling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 up-regulation occurring during dyskinesia expression. Linked articles: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetocen
dc.description.sponsorshipUniversità degli Studi di Ferrara (Grant/Award Number: FAR1891100)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationPisanò, C.A., Mercatelli, D., Mazzocchi, M., Brugnoli, A., Morella, I., Fasano, S., Zaveri, N.T., Brambilla, R., O’Keeffe, G.W., Neubig, R.R. and Morari, M. (2023) ‘Regulator of G‐Protein Signalling 4 (Rgs4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l ‐Dopa‐induced dyskinesia’, British Journal of Pharmacology, 180(7), pp. 927–942. Available at: https://doi.org/10.1111/bph.15730en
dc.identifier.doihttps://doi.org/10.1111/bph.15730en
dc.identifier.endpage942en
dc.identifier.issn0007-1188en
dc.identifier.issn1476-5381en
dc.identifier.issued7en
dc.identifier.journaltitleBritish Journal of Pharmacologyen
dc.identifier.startpage927en
dc.identifier.urihttps://hdl.handle.net/10468/15867
dc.identifier.volume180en
dc.language.isoenen
dc.publisherWiley; British Pharmacological Societyen
dc.relation.ispartofBritish Journal of Pharmacologyen
dc.rights© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-Non Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposesen
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectAT-403en
dc.subjectCCG-203920en
dc.subjectDyskinesiaen
dc.subjectL-Dopaen
dc.subjectNociceptin/orphanin FQen
dc.subjectRGS4en
dc.subjectOpioiden
dc.titleRegulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia en
dc.typeArticle (peer-reviewed)en
oaire.citation.issue7en
oaire.citation.volume180en
Files
Original bundle
Now showing 1 - 3 of 3
Thumbnail Image
Name:
British J Pharmacology - 2021 - Pisanò - Regulator of G‐Protein Signalling 4 RGS4.pdf
Size:
1.98 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download
Thumbnail Image
Name:
bph15730-sup-0001-supplementary information_full-lengh blot images.pdf
Size:
615.63 KB
Format:
Adobe Portable Document Format
Description:
Supporting information 1
Download
Thumbnail Image
Name:
bph15730-sup-0002-re_rev_supp mat_pisano bjp_2021_rgs4 ab and ccg specificity.docx
Size:
1004.46 KB
Format:
Microsoft Word XML
Description:
Supporting information 2
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
2.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Anatomy and Neuroscience - Journal Articles