G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease.
G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease.
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DOI：
10.3389/fphar.2015.00041
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发表时间：
2015
影响因子：
5.6
通讯作者：
Milligan G
中科院分区：
文献类型：
--
作者：
Divorty N;Mackenzie AE;Nicklin SA;Milligan G
G蛋白偶联受体35（GPR35）是一种孤儿受体，发现于1998年，通过与一系列疾病的相关性，作为潜在的治疗靶点引起了人们的兴趣。然而，缺乏药理学工具和缺乏令人信服的定义的内源性配体阻碍了了解必要的功能，利用它治疗。尽管几种内源性分子可以激活GPR35，但由于缺乏生物特异性、非生理学相关的效力和物种直系同源物选择性等原因，尚未证实其为关键的内源性配体。最近的进展已经鉴定了几种高度有效的合成激动剂和拮抗剂，以及对啮齿动物和人直系同源物具有等效效力的激动剂，其将用作工具化合物。同源性建模和突变研究提供了对配体结合模式以及某些配体物种选择性的可能原因的深入了解。在确定受体在疾病中的作用方面也取得了进展。过去，全基因组关联研究将GPR35与炎症性肠病、2型糖尿病和冠状动脉疾病等疾病联系起来。最近的功能研究表明，它参与了心力衰竭和缺氧、炎症、疼痛转导和突触传递等多种过程。本文综述了GPR35的分子药理学、下游信号传导和生理功能，并讨论了其作为治疗靶点的潜在应用。
G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome-wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target.
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