G-protein biased signaling agonists of Dopamine D3 receptor promote distinct activation patterns of ERK1/2.
G-protein biased signaling agonists of Dopamine D3 receptor promote distinct activation patterns of ERK1/2.
复制标题
多巴胺 D3 受体的 G 蛋白偏向信号激动剂促进 ERK1/2 的不同激活模式。
DOI：
10.1016/j.phrs.2022.106223
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发表时间：
2022
影响因子：
9.3
通讯作者：
Kortagere,Sandhya
中科院分区：
文献类型：
--
作者：
Xu,Wei;Bearoff,Frank;Kortagere,Sandhya
多巴胺D3受体（D3 R）在神经和精神疾病中具有因果作用。我们已经开发了一类新型的G蛋白偏向（GPB）信号D3 R激动剂，具有最小的β-arrestin 2（β arr 2）募集，并在帕金森病的啮齿动物模型中证明了疗效。这与无偏（UB）D3 R激动剂（如普拉克索）形成对比，后者招募β-抑制蛋白和G蛋白进行信号传导。在这项研究中，我们研究了GPB和UB激动剂对D3 R介导的ERK 1/2单磷酸化和双磷酸化激活的影响。我们利用稳定表达D3 R和β arr 2基因敲低（β arr 2KD）的神经元样SH-SY 5 Y细胞，研究Gi/o和β arr 2在D3 R激动剂诱导的ERK 1/2磷酸化模式中的作用。结果表明GPB和UB激动剂促进ERK 1/2的类似的早期和晚期单激活模式。相反，GPB和UB激动剂分别促进ERK 1/2的早期或早期和晚期双重激活。Gi/o主要促进ERK 1/2的早期双重激活，而β arr 2募集主要促进晚期双重激活。PKC在ERK 1/2的早期和晚期双重磷酸化中起重要作用。β arr 2KD显著增加GPB激动剂诱导的ERK 1/2的短期和长期双重磷酸化水平，而Gi/o和PKC抑制剂联合使用则可抑制该双重磷酸化水平。有趣的是，β arr 2KD显著降低UB激动剂对ERK 1/2的短期和长期双重磷酸化。总体而言，这项研究强调了D3 R的偏向性信号激动剂对ERK 1/2具有不同的作用，这可能有利于开发更好的药物。
Dopamine D3 receptors (D3R) have a causal role in neurological and psychiatric disorders. We have developed a novel class of G-protein biased (GPB) signaling D3R agonists with minimal β-arrestin2 (βarr2) recruitment and demonstrated efficacy in rodent model of Parkinson’s disease. This contrasts with unbiased (UB) D3R agonists like Pramipexole which recruit both β-arrestin and G-proteins for signaling. In this study, we investigated the effects of GPB and UB agonists on D3R mediated activation of mono and dual phosphorylation of ERK1/2. We used the neuronal-like SH-SY5Y cells stably expressing D3R and βarr2 knockdown (βarr2KD) to delineate the roles of Gi/oand βarr2 on phosphorylation patterns of ERK1/2 induced by D3R agonists. Results indicate GPB and UB agonists promote similar early and late phase mono activation patterns of ERK1/2. On the contrary, GPB and UB agonists promote either early or early and late phase dual activation of ERK1/2, respectively. The early phase dual activation of ERK1/2 is predominantly promoted by Gi/owhile the late phase dual activation by βarr2 recruitment. PKC plays a significant role in both the early and late phase dual phosphorylation of ERK1/2. βarr2KD significantly increased short- and long-term dual phosphorylation levels of ERK1/2 induced by GPB agonists which was inhibited by a combination of Gi/oand PKC inhibitors. Interestingly, βarr2KD significantly reduced the short and long-term dual phosphorylation of ERK1/2 by UB agonists. Overall, this study highlights that biased signaling agonists of D3R have differential effects on ERK1/2 which may be advantageous to develop better drugs.