The β-blocker Nebivolol Is a GRK/β-arrestin biased agonist.
The β-blocker Nebivolol Is a GRK/β-arrestin biased agonist.
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DOI：
10.1371/journal.pone.0071980
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Andresen BT
中科院分区：
文献类型：
--
作者：
Erickson CE;Gul R;Blessing CP;Nguyen J;Liu T;Pulakat L;Bastepe M;Jackson EK;Andresen BT
奈必洛尔是第三代β-肾上腺素能受体（β-AR）拮抗剂（β-阻滞剂），通过诱导一氧化氮（NO）产生而引起血管舒张。奈必洛尔诱导NO产生的机制尚不清楚，导致关于奈必洛尔药理作用的许多争议。卡维地洛是另一种诱导NO产生的β-受体阻滞剂。卡维地洛的一个突出药理学机制是不依赖于Gαs的偏性激动作用，涉及G蛋白偶联受体激酶（GRK）/β-抑制蛋白信号传导以及表皮生长因子受体（EGFR）和细胞外信号调节激酶（ERK）的下游激活。由于奈必洛尔和卡维地洛之间的药理学相似性，我们假设奈必洛尔也是一种GRK/β-抑制蛋白偏向性激动剂。我们利用仅表达β2-AR的小鼠胚胎成纤维细胞（MEF）和表达β1-和β2-AR且未检测到β3-AR的HL-1心肌细胞检验了这一假设。我们证实了先前的报道，奈必洛尔不会显著改变cAMP水平，因此不是一种经典的激动剂。此外，在两种细胞类型中，奈必洛尔诱导β-AR快速内化，表明奈必洛尔也不是经典的β-阻滞剂。此外，奈必洛尔处理导致ERK的时间依赖性磷酸化，其与卡维地洛难以区分，并且在持续时间上与异丙肾上腺素相似，但幅度不同。奈必洛尔介导的ERK磷酸化对普萘洛尔（非选择性β-AR阻断剂）、AG 1478（EGFR抑制剂）敏感，表明信号传导来自β-AR并涉及EGFR。此外，在MEFs中，奈必洛尔介导的ERK磷酸化对GRK 2的药理学抑制以及β-arrestin 1/2的siRNA敲低敏感。此外，奈必洛尔诱导β-arrestin 2从弥漫性染色模式重新分布为更强烈的点状斑点。我们得出结论，奈必洛尔是一种β2-AR，可能是β1-AR、GRK/β-arrestin偏向性激动剂，这表明奈必洛尔的一些独特临床有益作用可能是由于β1-和/或β2-AR的偏向性激动作用。
Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs.
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影响因子：
37.8
作者：
Dessy, C;Saliez, J;Balligand, JL
通讯作者：
Balligand, JL
影响因子：
9.3
作者：
Garbin, Ulisse;Fratta Pasini, Anna;Cominacini, Luciano
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影响因子：
5
作者：
NAMIKI, A;AKATSUKA, N
通讯作者：
AKATSUKA, N
影响因子：
3.6
作者：
Hamdani, Nazha;van der Velden, Jolanda
通讯作者：
van der Velden, Jolanda
影响因子：
3.2
作者：
Afonso, RA;Patarrao, RS;Carmo, MM
通讯作者：
Carmo, MM