Cell surface targeting of μ-δ opioid receptor heterodirners by RTP4
Cell surface targeting of μ-δ opioid receptor heterodirners by RTP4
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DOI：
10.1073/pnas.0804106105
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发表时间：
2008-10-14
影响因子：
11.1
通讯作者：
Devi, Lakshmi A.
中科院分区：
文献类型：
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作者：
Decaillot, Fabien M.;Rozenfeld, Raphael;Devi, Lakshmi A.
μ阿片样物质受体是G蛋白偶联受体，其介导临床使用的镇痛剂如吗啡的疼痛缓解作用。越来越多的证据表明，μ-δ阿片异二聚体具有不同于μ或δ同二聚体的药理学特征。由于异二聚体表现出独特的信号传导特性，调节其水平的蛋白质和机制对吗啡介导的生理学具有显著影响。我们报告的RTP 4，高尔基体伴侣，作为在细胞表面的异源二聚体的水平的调节器的特性。我们发现，与RTP 4的协会保护μ-δ受体的泛素化和降解。这导致表面异二聚体水平增加，从而影响信号传导。因此，阿片受体的寡聚体组织由RTP 4控制，这决定了它们的膜靶向和功能活性。这项工作是第一次报告的鉴定参与调节的家庭A GPCR异源二聚体的生物合成的伴侣。控制二聚化的RTP 4等因子的鉴定将为体内异二聚体的调节提供深入了解。这在调节其内源性配体的药理学和开发具有特定治疗作用的药物方面具有意义。
mu opioid receptors are G protein-coupled receptors that mediate the pain-relieving effects of clinically used analgesics, such as morphine. Accumulating evidence shows that mu-delta opioid heterodimers have a pharmacologic profile distinct from those of the mu or delta homodimers. Because the heterodimers exhibit distinct signaling properties, the protein and mechanism regulating their levels have significant effects on morphine-mediated physiology. We report the characterization of RTP4, a Golgi chaperone, as a regulator of the levels of heterodimers at the cell surface. We show that the association with RTP4 protects mu-delta receptors from ubiquitination and degradation. This leads to increases in surface heterodimer levels, thereby affecting signaling. Thus, the oligomeric organization of opioid receptors is controlled by RTP4, and this governs their membrane targeting and functional activity. This work is the first report of the identification of a chaperone involved in the regulation of the biogenesis of a family A GPCR heterodimer. The identification of such factors as RTP4 controlling dimerization will provide insight into the regulation of heterodimers in vivo. This has implications in the modulation of pharmacology of their endogenous ligands, and in the development of drugs with specific therapeutic effects.