Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor
Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor
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对毒蕈碱 M2 ACh 受体具有超生理功效的激动剂
DOI：
10.1111/bph.12003
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发表时间：
2013
影响因子：
7.3
通讯作者：
Mohr K
中科院分区：
文献类型：
--
作者：
Schrage R;Seemann WK;Klöckner J;Dallanoce C;Racké K;Kostenis E;De Amici M;Holzgrabe U;Mohr K
背景与目的人工激动剂可能比生理激动剂具有更高的受体激活效率。到目前为止，这种“超激动作用”很少被报道用于GPCR。Iperoxo是一种非常有效的毒蕈碱受体激动剂。我们假设iperoxo是一种“超级激动剂”。实验方法应用全细胞动态质量再分布、G蛋白活化测量、细胞表面激动剂结合评估和操作效力计算，将iperoxo和新合成的结构类似物与ACh在无标记M2毒蕈碱受体上的信号传导进行比较。Key ResultsIn CHO-hM 2细胞，iperoxo在Gi/Gs信号传导能力上显著超过ACh。在正构功能丧失突变体M2-Y1043.33A中，与ACh相比，iperoxo的最大作用几乎不受影响。在MRC-5人肺成纤维细胞的生理细胞环境中保留了“超激动作用”。结构信号的关系，包括iperoxo衍生物，无论是修改带正电荷的头部基团或改变尾巴表明，“superagonism”iperoxo的是机械的基础上通过两个orthosteric相互作用points.Conclusion和ImplicationsSuperphysiological激动剂的功效在毒蕈碱M2 ACh受体的平行激活。此外，提供了GPCR“超激动作用”的可能的潜在分子机制。我们认为，过氧化-类正构GPCR激活是一种新的途径，对一类新的受体激活剂。链接文章这篇文章是由Langmead和Christopoulos评论，pp.第353-356章这件事要查看此评论，请访问http://dx.doi.org/10.1111/bph.12142
Background and PurposeArtificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such ‘superagonism’ has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a ‘superagonist’.Experimental ApproachSignalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label‐free M2muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G‐protein activation, evaluation of cell surface agonist binding and computation of operational efficacies.Key ResultsIn CHO‐hM2cells, iperoxo significantly exceeds ACh in Gi/Gssignalling competence. In the orthosteric loss‐of‐function mutant M2‐Y1043.33A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. ‘Superagonism’ is preserved in the physiological cellular context of MRC‐5 human lung fibroblasts. Structure–signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that ‘superagonism’ of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points.Conclusion and ImplicationsSupraphysiological agonist efficacy at muscarinic M2ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR ‘superagonism’ is provided. We suggest that iperoxo‐like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators.Linked ArticleThis article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12142
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影响因子：
7.3
作者：
Michal, P;Lysíková, M;Tucek, S
通讯作者：
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DOI：
10.1124/jpet.104.075531
发表时间：
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影响因子：
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作者：
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影响因子：
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通讯作者：
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