Orphan G-Protein Coupled Receptor GPRC5B Is Critical for Lymphatic Development.
Orphan G-Protein Coupled Receptor GPRC5B Is Critical for Lymphatic Development.
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DOI：
10.3390/ijms23105712
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发表时间：
2022-05-20
影响因子：
5.6
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中科院分区：
文献类型：
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许多研究都集中在控制药物发育和生长的分子信号通路上，希望阐明有前途的药物靶点。G蛋白偶联受体（GPCR）是目前FDA批准的药物靶向的最大的膜受体家族，但仍有许多未开发的受体，包括没有已知生物配体或生理功能的孤儿GPCR。因此，我们试图阐明在淋巴管内皮细胞中以高水平表达的GPCR的干部，并鉴定了四种孤儿受体：GPRC 5 B、AGDRF 5/GPR 116、FZD 8和GPR 61。与血内皮细胞相比，GPRC 5 B是培养的人淋巴管内皮细胞（LECs）中表达最丰富的GPCR，原位RNA显微镜显示小鼠淋巴管中有较高的mRNA水平。在斑马鱼和小鼠中使用基因工程方法，我们表征了GPRC 5 B在淋巴发育中的功能。Morphant gprc 5 b斑马鱼表现出胸导管形成失败，而Gprc 5 b −/−小鼠患有胚胎水肿和与皮下水肿和充满血液的淋巴管相关的出血。与Gprc 5 +/+同窝对照相比，Gprc 5 b −/−胚胎表现出减弱的发育淋巴管生成。在出生后期间，约30%的Gprc 5 b −/−小鼠在断奶前生长受限或死亡，并伴有出生后心脏淋巴管生长的衰减。在培养的人原代LEC中，需要GPRC 5 B的表达来维持细胞增殖和活力。总的来说，我们确定了一个新的作用，富集的孤儿GPRC 5 B受体在鱼类，小鼠和人类细胞的淋巴管生成。阐明孤儿GPCR在神经营养学中的作用为发现治疗神经营养学相关病症（如水肿和癌症）的可药用靶点提供了新的途径。
Numerous studies have focused on the molecular signaling pathways that govern the development and growth of lymphatics in the hopes of elucidating promising druggable targets. G protein-coupled receptors (GPCRs) are currently the largest family of membrane receptors targeted by FDA-approved drugs, but there remain many unexplored receptors, including orphan GPCRs with no known biological ligand or physiological function. Thus, we sought to illuminate the cadre of GPCRs expressed at high levels in lymphatic endothelial cells and identified four orphan receptors: GPRC5B, AGDRF5/GPR116, FZD8 and GPR61. Compared to blood endothelial cells, GPRC5B is the most abundant GPCR expressed in cultured human lymphatic endothelial cells (LECs), and in situ RNAscope shows high mRNA levels in lymphatics of mice. Using genetic engineering approaches in both zebrafish and mice, we characterized the function of GPRC5B in lymphatic development. Morphant gprc5b zebrafish exhibited failure of thoracic duct formation, and Gprc5b−/− mice suffered from embryonic hydrops fetalis and hemorrhage associated with subcutaneous edema and blood-filled lymphatic vessels. Compared to Gprc5+/+ littermate controls, Gprc5b−/− embryos exhibited attenuated developmental lymphangiogenesis. During the postnatal period, ~30% of Gprc5b−/− mice were growth-restricted or died prior to weaning, with associated attenuation of postnatal cardiac lymphatic growth. In cultured human primary LECs, expression of GPRC5B is required to maintain cell proliferation and viability. Collectively, we identify a novel role for the lymphatic-enriched orphan GPRC5B receptor in lymphangiogenesis of fish, mice and human cells. Elucidating the roles of orphan GPCRs in lymphatics provides new avenues for discovery of druggable targets to treat lymphatic-related conditions such as lymphedema and cancer.
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影响因子：
3.5
作者：
Pulit SL;Stoneman C;Morris AP;Wood AR;Glastonbury CA;Tyrrell J;Yengo L;Ferreira T;Marouli E;Ji Y;Yang J;Jones S;Beaumont R;Croteau-Chonka DC;Winkler TW;GIANT Consortium;Hattersley AT;Loos RJF;Hirschhorn JN;Visscher PM;Frayling TM;Yaghootkar H;Lindgren CM
通讯作者：
Lindgren CM
影响因子：
4.6
作者：
Kurabayashi, Nobuhiro;Minh Dang Nguyen;Sanada, Kamon
通讯作者：
Sanada, Kamon
DOI：
10.1084/jem.20180528
发表时间：
2018-09-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mackie DI;Al Mutairi F;Davis RB;Kechele DO;Nielsen NR;Snyder JC;Caron MG;Kliman HJ;Berg JS;Simms J;Poyner DR;Caron KM
通讯作者：
Caron KM
DOI：
10.1038/nrd.2018.14
发表时间：
2018-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Oprea TI;Bologa CG;Brunak S;Campbell A;Gan GN;Gaulton A;Gomez SM;Guha R;Hersey A;Holmes J;Jadhav A;Jensen LJ;Johnson GL;Karlson A;Leach AR;Ma'ayan A;Malovannaya A;Mani S;Mathias SL;McManus MT;Meehan TF;von Mering C;Muthas D;Nguyen DT;Overington JP;Papadatos G;Qin J;Reich C;Roth BL;Schürer SC;Simeonov A;Sklar LA;Southall N;Tomita S;Tudose I;Ursu O;Vidovic D;Waller A;Westergaard D;Yang JJ;Zahoránszky-Köhalmi G
通讯作者：
Zahoránszky-Köhalmi G
DOI：
10.1038/nrd.2017.178
发表时间：
2017-12
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Hauser AS;Attwood MM;Rask-Andersen M;Schiöth HB;Gloriam DE
通讯作者：
Gloriam DE