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Inverse agonists to explore the mechanisms of metabotropic glutamate receptor activity

机译：反向激动剂探讨代谢谷氨酸受体活性的机制

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The most abundant excitatory neurotransmitter of the brain, glutamate, activates two sets of receptors: the ionotropic glutamate receptors responsible for the fast synaptic transmission and the metabotropic glutamate receptors (mGluRs) which regulate synaptic transmission. Thus, mGluRs are involved in fundamental physiological processes such as learning and memory, cardiac and movement control or pain. However, they also contribute to some neurological diseases. These receptors are then considered as good therapeutic targets. They share less than 10% sequence identity with the rhodopsin-related or the glucagon receptor-related receptors. Moreover, in addition to a heptahelical domain (HD) responsible for the coupling to G proteins, they possess a large extracellular domain containing the ligand binding site. Until recently, the functioning of these receptors was poorly understood. We have shown that several mGluRs displayed a constitutive activity, which was controlled by their C-terminal tail, and could be involved in long-term regulation of neuronal processes. Moreover, we showed that only noncompetitive allosteric compounds acting directly in the heptahelical domain were able to block this constitutive activity. These compounds allowed a better understanding of the mGluR activation process. Together with the recent determination of the crystal dimeric structure of the extracellular glutamate binding domain (BD) of mGluRl, our results led to a theoretical model for the functioning of this receptor.

机译：大脑中最丰富的兴奋性神经递质，谷氨酸激活两组受体：负责快速突触传递的离子型谷氨酸受体和调节突触传递的代谢谷氨酸受体（MGLURA）。因此，MGLURS参与基本的生理过程，如学习和记忆，心脏和运动控制或疼痛。然而，它们也有助于一些神经疾病。然后将这些受体视为良好的治疗靶标。它们与罗多蛋白酶相关或胰高血糖素受体相关的受体共享少于10％的序列同一性。此外，除了负责与G蛋白偶联的胚胎结构结构域（HD）之外，它们具有含有配体结合位点的大细胞外结构域。直到最近，这些受体的运作很差。我们已经表明，几种MGLURS显示了由其C末端尾部控制的组成型活性，并且可以参与神经元过程的长期调节。此外，我们表明，只有直接在渗透结构结构域中作用的非竞争性颠振复合物能够阻断这种组成型活性。这些化合物允许更好地了解MGLUR激活过程。与最近测定Mglull的细胞外谷氨酸结合结构域（BD）的晶体二聚体结构，我们的结果导致了该受体的功能的理论模型。

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《Fundaci髇 Dr. Antonio Esteve》|2003年||共10页
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L. Prezeau; M.L. Parmentier; R Carroll; J.P. Pin;
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中图分类蛋白质;
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Metabotropic glutamate receptors; Inverse agonist; Constitutive activity; Activation mechanism; Allosteric regulation;

机译：代谢谷氨酸受体;反向激动剂;组成型活性;激活机制;变构规则;

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1. Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]. [J] . Satow A, Maehara S, Ise S, The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics . 2008,第2期

机译：代谢型谷氨酸受体1拮抗剂与代谢型谷氨酸受体5拮抗剂和代谢型谷氨酸受体2/3激动剂在啮齿类动物中的药理作用：选择性变构代谢型谷氨酸受体1拮抗剂FTIDC的详细研究[4- [1-（ [2-氟吡啶-3-基）-5-甲基-1H-1,2,3-三唑-4-基] -N-异丙基-N-甲基-3,6-二氢吡啶-1（2H）-羧酰胺]。
2. Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice. [J] . Spooren WP, Gasparini F, van der-Putten-H, European Journal of Pharmacology: An International Journal . 2000,第1期

机译：LY314582（第2组代谢型谷氨酸受体激动剂）对苯环利定引起的代谢型谷氨酸受体2基因敲除小鼠的运动活性缺乏影响。
3. New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III [J] . Huynh Tri H. V., Erichsen Mette N., Tora Amelie S., Journal of Medicinal Chemistry . 2016,第3期

机译：新的4功能化谷氨酸类似物是代谢型谷氨酸受体亚型2的选择性激动剂或代谢型谷氨酸受体III组的选择性激动剂。
4. Inverse agonists to explore the mechanisms of metabotropic glutamate receptor activity [C] . L. Prezeau, M.L. Parmentier, R Carroll, Fundaci髇 Dr. Antonio Esteve . 2003

机译：反向激动剂探讨代谢谷氨酸受体活性的机制
5. Modulation of long -term potentiation and epileptiform activity in the rat dentate gyrus by the group II metabotropic glutamate receptor subtype mGluR3 [D] . Lea, Paul Milward, IV 2000

机译：II型代谢型谷氨酸受体亚型mGluR3对大鼠齿状回的长期增强和癫痫样活性的调节
6. Glutamate Acts as a Partial Inverse Agonist to Metabotropic Glutamate Receptor with a Single Amino Acid Mutation in the Transmembrane Domain [O] . Masataka Yanagawa, Takahiro Yamashita, Yoshinori Shichida 2013

机译：谷氨酸充当代谢型谷氨酸受体的部分逆激动剂跨膜结构域具有单个氨基酸突变。
7. Metabotropic glutamate receptor 3 neuroprotection A. Berent-Spillson and J. W. Russell Received June 12, 2006; revised manuscript received October 3, 2006; accepted October 5, 2006. Address correspondence and reprint requests to James W. Russell, Department of Neurology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201-1595, USA. E-mail: jruss@umich.edu Abbreviations used : APDC , 2 R ,4 R -4-aminopyrrolidine-2,4-dicarboxylate (specific metabotropic glutamate receptor 3 agonist) ; BSO , buthionine sulfoximine (GSH synthesis inhibitor) ; caspase , cysteine-requiring aspartate protease ; CysGly , cysteinylglycine (GSH degradation product) ; DAPI , 4′-6-diamidino-2-phenylindole ; DCF , dichlorodihydrofluorescein ; DCFDA , 5-(and 6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester ; DHE , dihydroethidium ; DRG , dorsal root ganglion ; FCCP , carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (electron transport uncoupler) ; GCP II/III , glutamate carboxypeptidase II/III ; GSH , glutathione ; GSH-EE , glutathione ethyl ester ; GST , glutathione-s-transferase ; H 2 O 2 , hydrogen peroxide ; HBSS , Hank’s balanced salt solution ; JC-1 , 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide ; MCB , monochlorobimane ; mGluR , metabotropic glutamate receptor ; NAAG , N -acetyl-aspartyl-glutamate ; PBS , phosphate-buffered saline ; PCD , programmed cell death ; Rh123 , rhodamine123 ; ROS , reactive oxygen species ; δψ μ , inner mitochondrial membrane potential . Metabotropic glutamate receptor 3 protects neurons from glucose-induced oxidative injury by increasing intracellular glutathione concentration [O] . Berent-Spillson Alison, Russell James W. 2007

机译：代谢型谷氨酸受体3神经保护a. Berent-spillson和J. W. Russell于2006年6月12日收到;修订稿于2006年10月3日收到; 2006年10月5日接受。美国马里兰州巴尔的摩市南格林街22号，马里兰大学医学院神经病学系James W. Russell的地址通信和重印申请。电子邮件：jruss@umich.edu使用的缩写：apDC，2R，4R-4-氨基吡咯烷-2,4-二羧酸酯（特异性代谢型谷氨酸受体3激动剂）; BsO，丁硫氨酸亚砜亚胺（GsH合成抑制剂）;半胱天冬酶，半胱氨酸需要的天冬氨酸蛋白酶; CysGly，半胱氨酰甘氨酸（GsH降解产物）; DapI，4'-6-二脒基-2-苯基吲哚; DCF，二氯二氢荧光素; DCFDa，5-（和6） - 氯甲基-2'，7'-二氯二氢荧光素二乙酸酯，乙酰酯; DHE，二氢乙锭; DRG，背根神经节; FCCp，羰基氰化物4-（三氟甲氧基）苯腙（电子传输解偶联剂）; GCp II / III，谷氨酸羧肽酶II / III;谷胱甘肽;谷胱甘肽; GsH-EE，谷胱甘肽乙酯; GsT，谷胱甘肽-s-转移酶; H 2 O 2，过氧化氢; HBss，Hank的平衡盐溶液; JC-1,5,5'，6,6'-四氯-1,1'，3,3'-四乙基苯并咪唑基酞菁碘化物; mCB，monochlorobimane; mGluR，代谢型谷氨酸受体; NaaG，N-乙酰基 - 天冬氨酰谷氨酸; pBs，磷酸盐缓冲盐水; pCD，程序性细胞死亡; Rh123，罗丹明123;活性氧，活性氧; δψμ，线粒体内膜电位。代谢型谷氨酸受体3通过增加细胞内谷胱甘肽浓度来保护神经元免受葡萄糖诱导的氧化损伤
8. Modulation of Long-Term Potentiation and Epileptiform Activity in the Rat Dentate Gyrus by the Group II Metabotropic Glutamate Receptor Subtype mGluR3 [R] . Lea, P. M. 2000

机译：II组代谢型谷氨酸受体亚型mGluR3对大鼠齿状回长期增强和癫痫样活动的调节

Inverse agonists to explore the mechanisms of metabotropic glutamate receptor activity

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