Therapeutic Opportunities and Challenges in Targeting the Orphan G Protein-Coupled Receptor GPR35.
Therapeutic Opportunities and Challenges in Targeting the Orphan G Protein-Coupled Receptor GPR35.
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DOI：
10.1021/acsptsci.0c00079
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发表时间：
2020-10-09
影响因子：
--
通讯作者：
Milligan G
中科院分区：
文献类型：
--
作者：
Quon T;Lin LC;Ganguly A;Tobin AB;Milligan G
GPR35是20多年前首次发现的a类视紫红质样G蛋白偶联受体（GPCR）。在此期间，在下肠和结肠、包括单核细胞和多种树突状细胞在内的多种免疫细胞以及背根神经节中发现了这种受体的强表达，这表明在一系列疾病中靶向这种受体有潜在的治疗机会。然而，GPR35在许多方面不同寻常，这对翻译路线提出了挑战。这些包括以下内容：(i)尽管大量的内源性配体被认为是该受体的激动剂伙伴，但它仍然被正式定义为“孤儿”GPCR。（ii）人类表达两种不同的蛋白质异构体序列，而啮齿动物只表达一种形式。（iii）人类和啮齿动物的GPR35同源物的药理学非常不同，大鼠和小鼠之间的GPR35的差异与这些物种和人类之间的差异一样明显。在此，我们对上述每个主题提供了观点，并提出了克服当前阻碍潜在翻译的挑战的方法。其中包括更好地了解物种选择性GPR35药理学的程度和分子基础，以及可以更好地定义假定GPR35配体的“靶上”和“靶外”效应的新型小鼠模型的制作，以及对人类同种异构体表达谱及其在组织和个体细胞水平上的意义的清晰理解。
GPR35 is a class A, rhodopsin-like G protein-coupled receptor (GPCR) first identified more than 20 years ago. In the intervening period, identification of strong expression in the lower intestine and colon, in a variety of immune cells including monocytes and a variety of dendritic cells, and in dorsal root ganglia has suggested potential therapeutic opportunities in targeting this receptor in a range of conditions. GPR35 is, however, unusual in a variety of ways that challenge routes to translation. These include the following: (i) Although a substantial range and diversity of endogenous ligands have been suggested as agonist partners for this receptor, it officially remains defined as an “orphan” GPCR. (ii) Humans express two distinct protein isoform sequences, while rodents express only a single form. (iii) The pharmacologies of the human and rodent orthologues of GPR35 are very distinct, with variation between rat and mouse GPR35 being as marked as that between either of these species and the human forms. Herein we provide perspectives on each of the topics above as well as suggesting ways to overcome the challenges currently hindering potential translation. These include a better understanding of the extent and molecular basis for species selective GPR35 pharmacology and the production of novel mouse models in which both “on-target” and “off-target” effects of presumptive GPR35 ligands can be better defined, as well as a clear understanding of the human isoform expression profile and its significance at both tissue and individual cell levels.
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影响因子：
30.8
作者：
Ellinghaus D;Jostins L;Spain SL;Cortes A;Bethune J;Han B;Park YR;Raychaudhuri S;Pouget JG;Hübenthal M;Folseraas T;Wang Y;Esko T;Metspalu A;Westra HJ;Franke L;Pers TH;Weersma RK;Collij V;D'Amato M;Halfvarson J;Jensen AB;Lieb W;Degenhardt F;Forstner AJ;Hofmann A;International IBD Genetics Consortium (IIBDGC);International Genetics of Ankylosing Spondylitis Consortium (IGAS);International PSC Study Group (IPSCSG);Genetic Analysis of Psoriasis Consortium (GAPC);Psoriasis Association Genetics Extension (PAGE);Schreiber S;Mrowietz U;Juran BD;Lazaridis KN;Brunak S;Dale AM;Trembath RC;Weidinger S;Weichenthal M;Ellinghaus E;Elder JT;Barker JN;Andreassen OA;McGovern DP;Karlsen TH;Barrett JC;Parkes M;Brown MA;Franke A
通讯作者：
Franke A
影响因子：
5.6
作者：
Divorty N;Mackenzie AE;Nicklin SA;Milligan G
通讯作者：
Milligan G
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole
影响因子：
76.2
作者：
Birring, Surinder S.;Wijsenbeek, Marlies S.;Morice, Alyn H.
通讯作者：
Morice, Alyn H.
DOI：
10.1016/j.bbrc.2017.09.113
发表时间：
2017-11-25
影响因子：
3.1
作者：
Guo, Ya Jie;Zhou, Yu Jie;Ou, Zhou Luo
通讯作者：
Ou, Zhou Luo