Coupling of the human A1 adenosine receptor to different heterotrimeric G proteins: evidence for agonist-specific G protein activation
Coupling of the human A1 adenosine receptor to different heterotrimeric G proteins: evidence for agonist-specific G protein activation
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DOI：
10.1038/sj.bjp.0705925
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发表时间：
2004-11-01
影响因子：
7.3
通讯作者：
Hill, SJ
中科院分区：
文献类型：
--
作者：
Cordeaux, Y;IJzerman, AP;Hill, SJ
1本研究调查了不同配体结构对激动剂通过A（1）腺苷受体激活Gi、Gs和Gq家族的鸟嘌呤核苷酸结合蛋白的能力的影响。2在表达该受体的CHO细胞中，使用毛喉素刺激的cAMP积累的抑制或增强作为终点来测量Gi的激活，并且在百日咳毒素（PTX）处理的细胞中，Gs，分别PTX处理的细胞中磷酸肌醇积累的刺激被用作Gq激活的指标。3 CPA（N-6-环戊基腺苷）、NECA（5 '-N-乙基-羧酰胺腺苷）和这些配体的八种类似物呈现一系列鸟嘌呤核苷酸结合蛋白（G蛋白）激活特征。一些配体仅能激活Gi（例如2 '脱氧CPA），一些主要激活Gi和Gs（并且仅弱激活Gq）（例如3'脱氧CPA），突出了核糖羟基在多种G蛋白的激动剂激活中的重要性。Cha NECA类似物5 '-N-环丙基-甲酰氨基腺苷、5'-N-环丁基-甲酰氨基腺苷和5 '-N-环戊基-甲酰氨基腺苷（CPeCA）也激活所有三种G蛋白，尽管它们激活Gs和Gq的能力（相对于CPA）随着取代基大小的增加而减少，使得CPeCA仅产生小的刺激，（100 μ M），但相对于CPA，在Gi和Gs是完全激动剂。5该研究表明，A（1）腺苷受体可以采用激动剂特异性构象，这是由配体结构的微小变化引起的，这导致Gi、Gs和Gq的差异激活。
1 The present study investigates the effect of varying ligand structure on the ability of agonists to activate guanine nucleotide-binding proteins of the Gi, Gs and Gq families via the A(1) adenosine receptor.2 In CHO cells expressing this receptor, inhibition or potentiation of forskolin-stimulated cAMP accumulation was used as an end point to measure the activation of Gi and, in Pertussis toxin (PTX)-treated cells, Gs, respectively. Stimulation of inositol phosphate accumulation in PTX-treated cells was used as an index of Gq activation.3 CPA (N-6-cyclopentyladenosine), NECA (5'-N-ethyl-carboxyamidoadenosine) and eight analogues of these ligands presented a range of guanine nucleotide-binding protein (G-protein)-activating profiles. Some ligands could only activate Gi (e.g. 2'deoxyCPA), some primarily Gi and Gs (and only weakly Gq) (e.g. 3'deoxyCPA), highlighting the importance of the ribose hydroxyls in agonist activation of multiple G proteins. CHA (N-6-cyclohexyladenosine) activated Gi, Gs and Gq, but was more efficacious than CPA in activating Gs.4 The NECA analogues 5'-N-cyclopropyl-carboxamidoadenosine, 5'-N-cyclobutyl-carboxamidoadenosine and 5'-N-cyclopentyl-carboxamidoadenosine (CPeCA) also activated all three G proteins, although their ability to activate Gs and Gq (relative to CPA) was reduced with increasing substituent size, such that CPeCA produced only a small stimulation (at 100 muM) at Gq, but was a full agonist, relative to CPA, at Gi and Gs.5 This study suggests that the A(1) adenosine receptor can adopt agonist-specific conformations, arising from small changes in ligand structure, which lead to the differential activation of Gi, Gs and Gq.