Dual action of neurokinin-1 antagonists on Mas-related GPCRs
Dual action of neurokinin-1 antagonists on Mas-related GPCRs
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DOI：
10.1172/jci.insight.89362
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发表时间：
2016-10-06
期刊：
影响因子：
8
通讯作者：
Lerner, Ethan A.
中科院分区：
文献类型：
--
作者：
Azimi, Ehsan;Reddy, Vemuri B.;Lerner, Ethan A.
将动物模型的发现转化为临床研究的挑战是众所周知的。这一挑战的一个例子是神经激肽-1受体（NK-1 R）拮抗剂在小鼠炎症模型中的惊人效果，以及它们在人类临床研究中同样惊人的失败。在这里，我们为这种二分法提供了一种解释：马斯相关的GPCR（Mrpcr）介导的炎症的某些方面，已被认为是由NK-1 R介导的。为了支持这一解释，我们表明，传统的NK-1 R拮抗剂对小鼠受体MrgprB 2具有脱靶活性，但对同源的人受体MRGPRX 2没有。一种不相关的三肽NK-1 R拮抗剂对MRGPRX 2具有双重活性。该三肽既抑制小鼠瘙痒，又抑制由MRGPRX 2的基础促分泌素激活引起的LAD-2人肥大细胞系的脱粒。MrkB的拮抗剂可以填补NK-1 R拮抗剂失败留下的空白。
The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2. An unrelated tripeptide NK-1R antagonist has dual activity on MRGPRX2. This tripeptide both suppresses itch in mice and inhibits degranulation from the LAD-2 human mast cell line elicited by basic secretagogue activation of MRGPRX2. Antagonists of Mrgprs may fill the void left by the failure of NK-1R antagonists.