The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization
The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization
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DOI：
10.1038/sj.emboj.7601193
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发表时间：
2006-07-12
期刊：
影响因子：
11.4
通讯作者：
Jockers, Ralf
中科院分区：
文献类型：
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作者：
Levoye, Angelique;Dam, Julie;Jockers, Ralf
大约400个无气味的G蛋白偶联受体（GPCR）中有三分之一仍然是孤儿。尽管这些受体中有相当数量的受体可能响应于有待鉴定的配体而抑制细胞信号，但它们也可能具有配体非依赖性功能。GPCR家族的几个成员已显示通过异源二聚化调节其他受体的功能。我们表明，GPR 50，孤儿GPCR，异二聚体组成和特异性与MT 1和MT 2褪黑激素受体，使用生物化学和生物物理方法在完整的细胞。而GPR 50和MT 2之间的关联并没有改变MT 2的功能，GPR 50废除高亲和力激动剂结合和G蛋白偶联到从事异二聚体的MT 1原聚体。GPR 50的大C-末端尾部的缺失抑制了GPR 50对MT 1的抑制作用，而不影响异源二聚化，表明该结构域调节调节蛋白与MT 1的相互作用。将孤儿GPCR与潜在的异源二聚化伴侣配对可能具有临床重要性，并且可能成为更好地理解孤儿GPCR功能的一般策略。
One-third of the similar to 400 nonodorant G protein-coupled receptors (GPCRs) are still orphans. Although a considerable number of these receptors are likely to transduce cellular signals in response to ligands that remain to be identified, they may also have ligand-independent functions. Several members of the GPCR family have been shown to modulate the function of other receptors through heterodimerization. We show that GPR50, an orphan GPCR, heterodimerizes constitutively and specifically with MT1 and MT2 melatonin receptors, using biochemical and biophysical approaches in intact cells. Whereas the association between GPR50 and MT2 did not modify MT2 function, GPR50 abolished high-affinity agonist binding and G protein coupling to the MT1 protomer engaged in the heterodimer. Deletion of the large C-terminal tail of GPR50 suppressed the inhibitory effect of GPR50 on MT1 without affecting heterodimerization, indicating that this domain regulates the interaction of regulatory proteins to MT1. Pairing orphan GPCRs to potential heterodimerization partners might be of clinical importance and may become a general strategy to better understand the function of orphan GPCRs.