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RGS4 negatively modulates Nociceptin/Orphanin FQ opioid receptor signaling: implication for L-Dopa induced dyskinesia

Pisanò, 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. 2021. RGS4 negatively modulates Nociceptin/Orphanin FQ opioid receptor signaling: implication for L-Dopa induced dyskinesia. British Journal of Pharmacology 10.1111/bph.15730

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Background and purpose Regulator of G-protein signal 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signaling. Here we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signaling and 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 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 upregulated RGS4 in the lesioned striatum. Conclusions and Implications RGS4 physiologically inhibits NOP receptor signaling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 upregulation occurring during dyskinesia expression.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Biosciences
Publisher: Wiley
ISSN: 0007-1188
Date of First Compliant Deposit: 16 November 2021
Date of Acceptance: 18 October 2021
Last Modified: 30 Jun 2022 16:38

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