Functional Selectivity of 6′-Guanidinonaltrindole (6′-GNTI) at κ-Opioid Receptors in Striatal Neurons
Functional Selectivity of 6′-Guanidinonaltrindole (6′-GNTI) at κ-Opioid Receptors in Striatal Neurons
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DOI：
10.1074/jbc.m113.476234
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发表时间：
2013-08-02
影响因子：
4.8
通讯作者：
Bohn, Laura M.
中科院分区：
文献类型：
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作者：
Schmid, Cullen L.;Streicher, John M.;Bohn, Laura M.
有相当多的证据表明，药物作用于kappa-阿片受体（KOR）可能是控制疼痛感知和调节奖励阈值的一种手段。作为一种G蛋白偶联受体（GPCR）， KOR的激活促进了G α (i/o)蛋白偶联和β -抑制素的募集。越来越明显的是，gpcr可以转导通过G蛋白途径和β -阻滞蛋白途径独立产生的信号；这种信号的配体依赖性分叉被称为“功能选择性”或“信号偏倚”。最近，一种KOR激动剂，6'-鸟嘌呤-萘啶醇（6'-GNTI），被证明比β -arrestin2募集更倾向于激活G蛋白介导的信号。因此，我们研究了纹状体神经元是否保留了这种配体偏差。虽然参考的KOR激动剂U69,593诱导ERK1/2和Akt磷酸化，但6'-GNTI仅激活纹状体神经元中的Akt通路。通过药理工具和β -arrestin2敲除小鼠，我们发现纹状体神经元中kor介导的ERK1/2磷酸化需要β -arrestin2，而Akt的激活依赖于G蛋白信号。这些发现揭示了在内源性神经元环境中可以观察到的KOR信号分叉点，并且可能被证明是在KOR中开发偏向性激动剂时的重要指标。
There is considerable evidence to suggest that drug actions at the kappa-opioid receptor (KOR) may represent a means to control pain perception and modulate reward thresholds. As a G protein-coupled receptor (GPCR), the activation of KOR promotes G alpha(i/o) protein coupling and the recruitment of beta-arrestins. It has become increasingly evident that GPCRs can transduce signals that originate independently via G protein pathways and beta-arrestin pathways; the ligand-dependent bifurcation of such signaling is referred to as "functional selectivity" or "signaling bias." Recently, a KOR agonist, 6'-guanidinonaltrindole (6'-GNTI), was shown to display bias toward the activation of G protein-mediated signaling over beta-arrestin2 recruitment. Therefore, we investigated whether such ligand bias was preserved in striatal neurons. Although the reference KOR agonist U69,593 induces the phosphorylation of ERK1/2 and Akt, 6'-GNTI only activates the Akt pathway in striatal neurons. Using pharmacological tools and beta-arrestin2 knock-out mice, we show that KOR-mediated ERK1/2 phosphorylation in striatal neurons requires beta-arrestin2, whereas Akt activation depends upon G protein signaling. These findings reveal a point of KOR signal bifurcation that can be observed in an endogenous neuronal setting and may prove to be an important indicator when developing biased agonists at the KOR.