The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling.
The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling.
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DOI：
10.1126/scisignal.aad0872
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发表时间：
2015-11-10
影响因子：
7.3
通讯作者：
Ferkey DM
中科院分区：
文献类型：
--
作者：
Likhite N;Jackson CA;Liang MS;Krzyzanowski MC;Lei P;Wood JF;Birkaya B;Michaels KL;Andreadis ST;Clark SD;Yu MC;Ferkey DM
蛋白质精氨酸甲基化调节真核细胞的多种功能，包括基因表达，DNA损伤反应和昼夜节律。我们发现，精氨酸残基内的第三个细胞内环的人D2多巴胺受体，这是保守的DOP-3受体的线虫线虫，被甲基化的蛋白质精氨酸甲基转移酶5（PRMT 5）。通过突变这些精氨酸残基，我们进一步表明，它们的甲基化增强了D2受体介导的抑制环磷酸腺苷（cAMP）信号在培养的人胚肾（HEK）293 T细胞。对prmt-5缺陷蠕虫的分析表明，甲基化促进了多巴胺介导的C. elegans通过DOP-3受体。除了描述以前未表征的调节GPCR（异源三聚体鸟嘌呤核苷酸结合蛋白偶联受体）信号传导的方法外，这些发现可能导致开发一类新的药理学疗法，通过改变这些关键蛋白的甲基化状态来调节GPCR信号传导。
Protein arginine methylation regulates diverse functions of eukaryotic cells, including gene expression, the DNA damage response, and circadian rhythms. We showed that arginine residues within the third intracellular loop of the human D2 dopamine receptor, which are conserved in the DOP-3 receptor in the nematode Caenorhabditis elegans, were methylated by protein arginine methyl-transferase 5 (PRMT5). By mutating these arginine residues, we further showed that their methylation enhanced the D2 receptor–mediated inhibition of cyclic adenosine monophosphate (cAMP) signaling in cultured human embryonic kidney (HEK) 293T cells. Analysis of prmt-5–deficient worms indicated that methylation promoted the dopamine-mediated modulation of chemosensory and locomotory behaviors in C. elegans through the DOP-3 receptor. In addition to delineating a previously uncharacterized means of regulating GPCR (heterotrimeric guanine nucleotide–binding protein–coupled receptor) signaling, these findings may lead to the development of a new class of pharmacological therapies that modulate GPCR signaling by changing the methylation status of these key proteins.