Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Antioxid Redox Signal. 2012 Nov 1;17(9):1163-77. doi: 10.1089/ars.2012.4517. Epub 2012 Jul 10.
Morphine signaling via the μ-opioid receptor (MOR) is coupled to redox-dependent zinc release from endogenous stores. Thus, MOR activation stimulates the complex formed by RGSZ2 (a regulator of G protein signaling) and neural nitric oxide synthase (nNOS) to produce NO, and to recruit PKCγ and Raf-1 in a zinc-dependent manner. Accordingly, we investigated whether redox regulation of zinc metabolism was unique to the MOR, or if it is a signaling mechanism shared by G-protein coupled receptors (GPCRs).
A physical interaction with the RGSZ2-nNOS complex was detected for the following GPCRs: neuropeptides, MOR and δ-opioid (DOR); biogenic amines, 5HT1A, 5HT2A, α2A, D1 and D2; acetylcholine, muscarinic M2 and M4; excitatory amino acid glutamate, mGlu2 and mGlu5; and derivatives of arachidonic acid (anandamide), CB1. Agonist activation of these receptors induced the release of zinc ions from the RGSZ2 zinc finger via a nNOS/NO-dependent mechanism, recruiting PKCγ and Raf-1 to the C terminus or the third internal loop of the GPCR.
A series of GPCRs share an unexpected mechanistic feature, the nNOS/NO-dependent regulation of zinc ion signaling via a redox mechanism. The RGSZ2 protein emerges as a potential redox zinc switch that converts NO signals into zinc signals, thereby able to modulate the function of redox sensor proteins like PKCγ or Raf-1.
Redox mechanisms are crucial for the successful propagation of GPCR signals in neurons. Thus, dysfunctions of GPCR-regulated NO/zinc signaling may contribute to neurodegenerative and mood disorders such as Alzheimer's disease and depression.
通过 μ 阿片受体 (MOR) 的吗啡信号与来自内源性储存的依赖于氧化还原的锌释放偶联。因此，MOR 激活刺激由 RGSZ2（G 蛋白信号转导的调节剂）和神经型一氧化氮合酶（nNOS）形成的复合物产生 NO，并以依赖于锌的方式募集 PKCγ 和 Raf-1。因此，我们研究了氧化还原调节锌代谢是否仅对 MOR 是独特的，或者它是否是 G 蛋白偶联受体（GPCR）共享的信号机制。
检测到以下 GPCR 与 RGSZ2-nNOS 复合物的物理相互作用：神经肽、MOR 和 δ-阿片受体（DOR）；生物胺，5HT1A、5HT2A、α2A、D1 和 D2；乙酰胆碱，毒蕈碱 M2 和 M4；兴奋性氨基酸谷氨酸，mGlu2 和 mGlu5；以及花生四烯酸（大麻素）的衍生物，CB1。这些受体的激动剂激活通过 nNOS/NO 依赖性机制诱导锌离子从 RGSZ2 锌指中释放，从而募集 PKCγ 和 Raf-1 到 GPCR 的 C 末端或第三内部环。
一系列 GPCR 具有意想不到的机制特征，即 nNOS/NO 依赖性通过氧化还原机制调节锌离子信号。RGSZ2 蛋白作为潜在的氧化还原锌开关出现，可将 NO 信号转换为锌信号，从而能够调节 PKCγ 或 Raf-1 等氧化还原传感器蛋白的功能。
氧化还原机制对于 GPCR 信号在神经元中的成功传递至关重要。因此，GPCR 调节的 NO/锌信号的功能障碍可能导致神经退行性疾病和情绪障碍，如阿尔茨海默病和抑郁症。
