Rubiscolins are naturally occurring G protein-biased delta opioid receptor peptides
Rubiscolins are naturally occurring G protein-biased delta opioid receptor peptides
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DOI：
10.1016/j.euroneuro.2018.12.013
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发表时间：
2019-03-01
影响因子：
5.6
通讯作者：
van Rijn, Richard M.
中科院分区：
文献类型：
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作者：
Cassell, Robert J.;Mores, Kendall L.;van Rijn, Richard M.
β-抑制蛋白对 G 蛋白偶联受体运输、信号传导和生理行为的影响在过去十年中得到了广泛的认可。许多研究将与使用天然和合成阿片类药物相关的副作用（例如呼吸抑制和便秘）归因于β-抑制蛋白的过度募集。这些发现导致偏向阿片类小分子激动剂的开发，这些激动剂不招募 β-抑制蛋白，仅激活经典 G 蛋白途径。类似的偏向G蛋白的小分子阿片类药物被发现存在于自然界中，特别是在卡痛叶中，而丹参中的阿片类药物已作为合成其他偏向G蛋白的阿片类药物的模板。在这里，我们首次报告了天然存在的肽，它们选择性激活多片受体的 G 蛋白信号传导途径，但 β-抑制蛋白的募集量最少。具体来说，我们发现作为植物蛋白 rubisco 裂解产物产生的 rubiscolin 肽可结合并激活多片受体上的 G 蛋白信号传导。然而，与天然存在的多片肽亮氨酸脑啡肽和德尔啡肽 II 不同，红比斯可林肽仅非常微弱地募集 β-抑制蛋白 2，并且在 d 阿片受体处无法检测到 β-抑制蛋白 1 的募集。 (c) 2018 Elsevier B.V. 和 ECNP。版权所有。
The impact that beta-arrestin proteins have on G protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of beta-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit beta-arrestin, activating only the canonical G protein pathway. Similar G protein-biased small molecule opioids have been found to occur in nature, particularly within kratom, and opioids within salvia have served as a template for the synthesis of other G proteinbiased opioids. Here, we present the first report of naturally occurring peptides that selectively activate G protein signaling pathways at dopioid receptors, but with minimal beta-arrestin recruitment. Specifically, we find that rubiscolin peptides, which are produced as cleavage products of the plant protein rubisco, bind to and activate G protein signaling at dopioid receptors. However, unlike the naturally occurring dopioid peptides leu-enkephalin and deltorphin II, the rubiscolin peptides only very weakly recruit beta-arrestin 2 and have undetectable recruitment of beta-arrestin 1 at the d opioid receptor. (c) 2018 Elsevier B. V. and ECNP. All rights reserved.