Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism.
Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism.
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DOI：
10.1016/j.neuropharm.2015.02.007
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发表时间：
2015-06
影响因子：
4.7
通讯作者：
Wroblewski JT
中科院分区：
文献类型：
--
作者：
Hathaway HA;Pshenichkin S;Grajkowska E;Gelb T;Emery AC;Wolfe BB;Wroblewski JT
大多数关于代谢型谷氨酸（mGlu）受体1功能的现有研究集中在G蛋白介导的结果。然而，与其他G蛋白偶联受体（GPCR）类似，越来越明显的是，mGlu 1受体信号转导是多维的，并不总是涉及G蛋白激活。以前，在转染的CHO细胞中，我们发现mGlu 1受体激活G蛋白非依赖性，β-抑制蛋白依赖性信号转导机制，一些mGlu 1受体配体不能刺激这种反应。在这里，我们着手调查这些研究结果的生理相关性，在一个本地系统使用小脑颗粒细胞的原代培养。我们测试了一组化合物刺激两种mGlu 1受体介导的结果的能力：（1）在营养支持撤回后保护细胞活力降低和（2）G蛋白介导的磷酸肌醇（PI）水解。我们报告说，常用的mGlu 1受体配体使君子，DHPG，和ACPD是完全偏向PI水解，不诱导mGlu 1受体刺激的神经保护。另一方面，包括谷氨酸、天冬氨酸、半胱氨酸、半胱氨酸亚磺酸和同型半胱氨酸的内源性化合物刺激这两种反应。这些结果表明，一些常用的mGlu 1受体配体是偏性激动剂，刺激只有一小部分的mGlu 1受体介导的神经元反应。这强调了在研究GPCR功能时利用多种激动剂和测定的重要性。
The majority of existing research on the function of metabotropic glutamate (mGlu) receptor 1 focuses on G protein-mediated outcomes. However, similar to other G protein-coupled receptors (GPCR), it is becoming apparent that mGlu1 receptor signaling is multi-dimensional and does not always involve G protein activation. Previously, in transfected CHO cells, we showed that mGlu1 receptors activate a G protein-independent, β-arrestin-dependent signal transduction mechanism and that some mGlu1 receptor ligands were incapable of stimulating this response. Here we set out to investigate the physiological relevance of these findings in a native system using primary cultures of cerebellar granule cells. We tested the ability of a panel of compounds to stimulate two mGlu1 receptor-mediated outcomes: (1) protection from decreased cell viability after withdrawal of trophic support and (2) G protein-mediated phosphoinositide (PI) hydrolysis. We report that the commonly used mGlu1 receptor ligands quisqualate, DHPG, and ACPD are completely biased towards PI hydrolysis and do not induce mGlu1 receptor-stimulated neuroprotection. On the other hand, endogenous compounds including glutamate, aspartate, cysteic acid, cysteine sulfinic acid, and homocysteic acid stimulate both responses. These results show that some commonly used mGlu1 receptor ligands are biased agonists, stimulating only a fraction of mGlu1 receptor-mediated responses in neurons. This emphasizes the importance of utilizing multiple agonists and assays when studying GPCR function.
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大鼠脑 G 蛋白偶联谷氨酸受体的克隆、表达和基因结构
影响因子：
56.9
作者：
HOUAMED, KM;KUIJPER, JL;HAGEN, FS
通讯作者：
HAGEN, FS
影响因子：
3.6
作者：
Notartomaso S;Zappulla C;Biagioni F;Cannella M;Bucci D;Mascio G;Scarselli P;Fazio F;Weisz F;Lionetto L;Simmaco M;Gradini R;Battaglia G;Signore M;Puliti A;Nicoletti F
通讯作者：
Nicoletti F
DOI：
10.1080/147342202753203087
发表时间：
2002-01-01
期刊：
Cerebellum (London, England)
影响因子：
--
作者：
Contestabile, Antonio
通讯作者：
Contestabile, Antonio
影响因子：
3.6
作者：
Emery, Andrew C.;DiRaddo, John O.;Wroblewski, Jarda T.
通讯作者：
Wroblewski, Jarda T.
DOI：
10.1038/nrd3024
发表时间：
2010-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
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