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RGS4 negatively modulates Nociceptin/Orphanin FQ opioid receptor signaling: implication for L-Dopa induced dyskinesia
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  • Clarissa Anna Pisanò,
  • Daniela Mercatelli,
  • Martina Mazzocchi,
  • Alberto Brugnoli,
  • Ilaria Morella,
  • Stefania Fasano,
  • Nurulain Zaveri,
  • Riccardo Brambilla,
  • Gerard O’Keeffe ,
  • Richard D Neubig,
  • Michele Morari
Clarissa Anna Pisanò
University of Ferrara

Corresponding Author:[email protected]

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Daniela Mercatelli
University of Ferrara
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Martina Mazzocchi
University College Cork
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Alberto Brugnoli
University of Ferrara
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Ilaria Morella
Cardiff University
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Stefania Fasano
Cardiff University
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Nurulain Zaveri
Astraea Therapeutics
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Riccardo Brambilla
Cardiff University
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Gerard O’Keeffe
University College Cork
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Richard D Neubig
Michigan State University
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Michele Morari
University of Ferrara
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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 opioid (NOP) receptor signaling and whether 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 RGS4 inhibitor, CCG-203920, and D1-stimulated cAMP or pERK responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and levodopa 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 levodopa. Levodopa acutely upregulated RGS4 in the lesioned striatum. Conclusions and Implications: RGS4 physiologically inhibits NOP receptor signaling and an RGS4 inhibitor enhances NOP responses. Furthermore, an RGS4 inhibitor improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of upregulation of striatal RGS4 levels occurring during dyskinesia expression.
24 Feb 2021Submitted to British Journal of Pharmacology
24 Feb 2021Submission Checks Completed
24 Feb 2021Assigned to Editor
26 Feb 2021Reviewer(s) Assigned
27 Mar 2021Review(s) Completed, Editorial Evaluation Pending
31 Mar 2021Editorial Decision: Revise Minor
08 Sep 20211st Revision Received
11 Sep 2021Submission Checks Completed
11 Sep 2021Assigned to Editor
14 Sep 2021Reviewer(s) Assigned
02 Oct 2021Review(s) Completed, Editorial Evaluation Pending
05 Oct 2021Editorial Decision: Revise Minor
11 Oct 20212nd Revision Received
16 Oct 2021Submission Checks Completed
16 Oct 2021Assigned to Editor
18 Oct 2021Editorial Decision: Accept
12 Nov 2021Published in British Journal of Pharmacology. 10.1111/bph.15730