Gα Protein Signaling Bias at Serotonin 1A Receptor.
Gα Protein Signaling Bias at Serotonin 1A Receptor.
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DOI：
10.1124/molpharm.123.000722
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发表时间：
2023-11
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
5-羟色胺1A受体(5-HT1AR)参与多种中枢和外周功能，包括睡眠、温度动态平衡、情绪处理和应激反应，是临床上相关的靶点。5-α受体是一种G蛋白偶联受体，可激活大量G-HT1AR I/o/z家族成员，在不同的治疗方法下，可能参与多种细胞内信号转导通路的调节。在这里，我们应用了一种基于细胞的生物发光共振能量转移分析来量化10种结构不同的5-HT1AR激动剂如何通过差异刺激Gαi/o/z家族成员来施加有偏见的信号。我们对每个Gαi/o/z蛋白激活的浓度-反应分析显示，与参考的5-羟色胺、5-羟色胺相比，选定的激动剂具有独特的效力和功效。总体而言，我们对信号偏倚的分析确定了具有类似G蛋白激活选择性的配体组，以及具有独特选择性特征的药物。例如，我们观察到F-15599对Gαi3的激活有强烈的偏向，这在所测试的激动剂中是独一无二的：当比较F-15599对Gαi3和Gαi2的激活时，我们发现偏置系数为+2.19，而8-羟基-2-(二正丙氨基)四氢呋喃的偏向系数为-0.29。同样，伏替西汀对Gαz和GαOA的偏倚因子为+1.06，而维拉唑酮为-1.38。考虑到替代信号通路是在每个Gα蛋白的下游调节的，我们的数据表明，受试激动剂的独特药理特性可能导致多种无关的细胞结果。需要进一步的研究来揭示这种类型的配体偏向如何影响细胞反应，并阐明每种药物治疗概况和副作用的分子机制。5-羟色胺1a受体(5-HT1AR)激活Gi/o/z蛋白家族的几个成员。在这里，我们研究了10种结构不同和临床相关的作用于5-HT1AR的激动剂，并确定了G蛋白之间独特的偏向模式。考虑到它们细胞内效应器和信号特性的多样性，这些数据揭示了治疗和不良作用的新机制。
Serotonin 1A receptor (5-HT1AR) is a clinically relevant target because of its involvement in several central and peripheral functions, including sleep, temperature homeostasis, processing of emotions, and response to stress. As a G protein coupled receptor (GPCR) activating numerous Gαi/o/z family members, 5-HT1AR can potentially modulate multiple intracellular signaling pathways in response to different therapeutics. Here, we applied a cell-based bioluminescence resonance energy transfer assay to quantify how ten structurally diverse 5-HT1AR agonists exert biased signaling by differentially stimulating Gαi/o/z family members. Our concentration-response analysis of the activation of each Gαi/o/z protein revealed unique potency and efficacy profiles of selected agonists when compared with the reference 5-hydroxytryptamine, serotonin. Overall, our analysis of signaling bias identified groups of ligands sharing comparable G protein activation selectivity and also drugs with unique selectivity profiles. We observed, for example, a strong bias of F-15599 toward the activation of Gαi3 that was unique among the agonists tested: we found a biased factor of +2.19 when comparing the activation of Gαi3 versus Gαi2 by F-15599, while it was -0.29 for 8-hydroxy-2-(di-n-propylamino) tetralin. Similarly, vortioxetine showed a biased factor of +1.06 for Gαz versus GαoA, while it was -1.38 for vilazodone. Considering that alternative signaling pathways are regulated downstream of each Gα protein, our data suggest that the unique pharmacological properties of the tested agonists could result in multiple unrelated cellular outcomes. Further investigation is needed to reveal how this type of ligand bias could affect cellular responses and to illuminate the molecular mechanisms underlying therapeutic profile and side effects of each drug. Serotonin 1a receptor (5-HT1AR) activates several members of the Gi/o/z protein family. Here, we examined ten structurally diverse and clinically relevant agonists acting on 5-HT1AR and identified distinctive bias patterns among G proteins. Considering the diversity of their intracellular effectors and signaling properties, this data reveal novel mechanisms underlying both therapeutic and undesirable effects.
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影响因子：
14.9
作者：
Kooistra AJ;Mordalski S;Pándy-Szekeres G;Esguerra M;Mamyrbekov A;Munk C;Keserű GM;Gloriam DE
通讯作者：
Gloriam DE
影响因子：
3.4
作者：
Garcia-Garcia, Alvaro L.;Newman-Tancredi, Adrian;Leonardo, E. David
通讯作者：
Leonardo, E. David
影响因子：
3.6
作者：
Berg, KA;Maayani, S;Clarke, WP
通讯作者：
Clarke, WP
影响因子：
7.3
作者：
Llado-Pelfort, L.;Assie, M-B;Celada, P.
通讯作者：
Celada, P.
影响因子：
4.8
作者：
Hollins B;Kuravi S;Digby GJ;Lambert NA
通讯作者：
Lambert NA