Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia.
Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia.
复制标题
G 蛋白信号传导调节器 4 (RGS4) 负向调节伤害感受肽/孤啡肽 FQ 阿片受体信号传导：对左旋多巴诱导的运动障碍的影响。
DOI：
10.1111/bph.15730
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发表时间：
2023
影响因子：
7.3
通讯作者：
Pisanò CA
中科院分区：
文献类型：
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作者：
Pisanò CA
研究背景与目的G蛋白信号调节因子4（Regulator of G‐protein signaling 4，RGS 4）是一种信号转导蛋白，可促进Gαi/o和Gα q亚基的内源性GT3活性，抑制GPCR信号转导。在这里，我们研究RGS 4是否调节FQ（N/OFQ）阿片（NOP）受体信号传导中的伤害感受素/阿片肽，以及这种调节是否与l-多巴诱导的运动障碍相关。实验方法用N/OFQ和小分子NOP激动剂AT-403攻击转染NOP、NOP/RGS 4或NOP/RGS 19的HEK 293 T细胞，使用D1刺激的cAMP水平作为读数。在实验性RGS 4化学探针CCG-203920存在下，用N/OFQ或AT-403激发原代大鼠纹状体神经元和成年小鼠纹状体切片，并监测D1刺激的cAMP或磷酸化细胞外信号调节激酶1/2（pERK）反应。在体内，将CCG-203920与AT-403和l-多巴共同给予6-羟基多巴胺半脑损伤大鼠，并测量了运动障碍运动、运动障碍的纹状体生化相关性（pERK和pGluR 1水平）和纹状体RGS 4水平。关键结果RGS 4表达降低了NOFQ和AT-403在HEK 293 T细胞中的效力和功效。CCG-203920增加原代大鼠纹状体神经元中的N/OFQ效力，并增强小鼠纹状体切片中的AT-403反应。CCG-203920增强了AT-403介导的对运动障碍及其生化相关性的抑制，而不影响其运动改善作用。单侧多巴胺耗竭导致双侧RGS 4水平降低，这被逆转为β-Dopa.l-Dopa在受损的striatum.Conclusions和ImplicationsRGS 4生理上抑制NOP受体信号传导。CCG-203920增强了NOP反应，改善了NOP受体激动剂的抗运动障碍潜力，减轻了运动障碍表达过程中发生的纹状体RGS 4上调的影响。链接文章这篇文章是阿片类药物流行时阿片类药物药理学进展主题问题的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc
Background and PurposeRegulator of G‐protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/oand Gαqsubunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance forl‐Dopa‐induced dyskinesia.Experimental ApproachHEK293T 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 andl‐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 ResultsRGS4 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 byl‐Dopa.l‐Dopa acutely up‐regulated RGS4 in the lesioned striatum.Conclusions and ImplicationsRGS4 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 ARTICLESThis 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/issuetoc