孤儿 G 蛋白偶联受体（GPCRs）：生物学功能和潜在的药物靶点。
Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets.
机构信息
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, China.
出版信息
Acta Pharmacol Sin. 2012 Mar;33(3):363-71. doi: 10.1038/aps.2011.210. Epub 2012 Feb 27.
Abstract
The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. GPCRs are the most successful targets of modern medicine, and approximately 36% of marketed pharmaceuticals target human GPCRs. However, the endogenous ligands of more than 140 GPCRs remain unidentified, leaving the natural functions of those GPCRs in doubt. These are the so-called orphan GPCRs, a great source of drug targets. This review focuses on the signaling transduction pathways of the adhesion GPCR family, the LGR subfamily, and the PSGR subfamily, and their potential functions in immunology, development, and cancers. In this review, we present the current approaches and difficulties of orphan GPCR deorphanization and characterization.
摘要
G 蛋白偶联受体（GPCR）超家族至少包含 800 种七跨膜受体，参与多种生理和病理功能。GPCR 是现代医学最成功的靶点，约 36%的上市药物针对人类 GPCR。然而，超过 140 种 GPCR 的内源性配体仍未被识别，这些 GPCR 的自然功能仍存在疑问。这些 GPCR 被称为孤儿 GPCR，是药物靶点的重要来源。本文主要关注黏附 GPCR 家族、LGR 亚家族和 PSGR 亚家族的信号转导途径及其在免疫学、发育和癌症中的潜在功能。本文介绍了目前孤儿 GPCR 鉴定和特征分析的方法和难点。
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1
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Nat Rev Drug Discov. 2011 Aug 1;10(8):579-90. doi: 10.1038/nrd3478.
2
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Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11452-7. doi: 10.1073/pnas.1106083108. Epub 2011 Jun 21.
3
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Adv Exp Med Biol. 2010;706:157-66. doi: 10.1007/978-1-4419-7913-1_14.
4
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Adv Exp Med Biol. 2010;706:121-7. doi: 10.1007/978-1-4419-7913-1_10.
5
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Adv Exp Med Biol. 2010;706:14-36. doi: 10.1007/978-1-4419-7913-1_2.
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