Department of Infection and Immunity, Luxembourg Institute of Health (LIH), rue Henri Koch 29, L-4354, Esch-sur-Alzette, Luxembourg.
Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115, Bonn, Germany.
Nat Commun. 2020 Jun 19;11(1):3033. doi: 10.1038/s41467-020-16664-0.
Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.
内源性阿片肽和处方类阿片药物通过激活阿片受体来调节疼痛、焦虑和应激，目前阿片受体被分为四种亚型。在这里，我们证明了 ACKR3/CXCR7，此前被认为是一种趋化因子的非典型清道夫受体，也是阿片肽的广谱清道夫。从进化的角度来看，ACKR3 介于趋化因子和阿片受体之间，与经典阿片受体一起存在于各种脑区。从功能上看，ACKR3 是多种阿片肽的清道夫受体，尤其是内啡肽和强啡肽，减少了它们与经典阿片受体的结合。ACKR3 不受处方类阿片药物的调节，但我们发现 ACKR3 选择性的亚纳摩尔竞争肽 LIH383 可以抑制 ACKR3 对大鼠脑中阿片肽的负调节作用，并增强它们对经典受体的活性，这可能为阿片类相关疾病开辟新的治疗途径。总之，我们的研究结果揭示了 ACKR3 是一种具有跨家族配体选择性的非典型阿片受体。
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