代谢型谷氨酸受体5与神经系统疾病的研究进展
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摘要
代谢型谷氨酸受体5(mGluR5)作为重要的mGluR之一,通过第二信使发挥生物学效应。mGluR5以二聚体形式主要分布于大脑皮质、海马和纹状体等区域,通过激活磷脂酶C-肌醇1,4,5-三磷酸-甘油二酯-Ca~(2+)和磷脂酰肌醇3-激酶-哺乳动物雷帕霉素靶蛋白等信号通路,参与神经兴奋性网络调节、神经发生以及与学习记忆相关的突触可塑性形成。近来研究证实,mGluR5在神经性疾病中发挥着重要作用。研究表明,mGluR5的过度激活或抑制与多种神经性疾病的病理过程密切相关。多种选择性激活或抑制mGluR5活性的药物已被应用于神经性疾病的治疗。
The metabotropic glutamate receptor 5(m Glu R5), one of the most important m Glu Rs, exerts a biological effect through the second messenger. mGluR5 is mainly distributed in the cerebral cortex,hippocampus, and striatum in the form of dimers. It participates in neuronal excitability network regulation,neurogenesis, and synaptic plasticity associated with learning and memory by activating signaling pathways such as protein kinase C-inositol 1, 4, 5-triphosphate-diacylglycerol-Ca2+and phosphatidylinositol 3-kinasemammalian target of Rapamycin. Recently, mGluR5 has been confirmed to play an important role in diseases of the nervous system. Studies have shown that over-activation or inhibition of mGluR5 is closely related to the pathological processes of a variety of neurological diseases. A variety of drugs that selectively activate or inhibit m Glu R5 activity have been used in the treatment of neurological diseases.
The metabotropic glutamate receptor 5(m Glu R5), one of the most important m Glu Rs, exerts a biological effect through the second messenger. mGluR5 is mainly distributed in the cerebral cortex,hippocampus, and striatum in the form of dimers. It participates in neuronal excitability network regulation,neurogenesis, and synaptic plasticity associated with learning and memory by activating signaling pathways such as protein kinase C-inositol 1, 4, 5-triphosphate-diacylglycerol-Ca2+and phosphatidylinositol 3-kinasemammalian target of Rapamycin. Recently, mGluR5 has been confirmed to play an important role in diseases of the nervous system. Studies have shown that over-activation or inhibition of mGluR5 is closely related to the pathological processes of a variety of neurological diseases. A variety of drugs that selectively activate or inhibit m Glu R5 activity have been used in the treatment of neurological diseases.
引文
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[2]Niswender CM, Conn PJ. Metabotropic glutamate receptors:physiology,pharmacology,and disease[J]. Annu Rev Pharmacol Toxicol,2010,50:295-322.
[3]Vafabakhsh R,Levitz J,Isacoff EY. Conformational dynamics of a class C G-protein-coupled receptor[J]. Nature,2015,524(7566):497-501.
[4]Doumazane E, Schol er P, Fabre L, Zwier JM,Trinquet E,Pin JP,et al. Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors[J]. Proc Natl Acad Sci USA,2013,110(15):E1416-E1425.
[5]Testa CM,Standaert DG,Young AB,Penney JBJr.Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat[J]. J Neurosci,1994,14(5 Pt 2):3005-3018.
[6]Tanabe Y,Nomura A,Masu M,Shigemoto R,Mizuno N, Nakanishi S. Signal transduction,pharmacological properties,and expression patterns of two rat metabotropic glutamate receptors,mGluR3 and mGluR4[J]. J Neurosci,1993,13(4):1372-1378.
[7]Gerrow K,Triller A. Synaptic stability and plasticity in a floating world[J]. Curr Opin Neurobiol,2010,20(5):631-639.
[8]Kang SJ, Kaang BK. Metabotropic glutamate receptor dependent long-term depression in the cortex[J]. Korean J Physiol Pharmacol,2016,20(6):557-564.
[9]Waung MW, Huber KM. Protein translation in synaptic plasticity:m Glu R-LTD,fragile X[J]. Curr Opin Neurobiol,2009,19(3):319-326.
[10]Mutel V,Ellis GJ,Adam G,Chaboz S,Nilly A,Messer J,et al. Characterization of[3H]quisqualate binding to recombinant rat metabotropic glutamate1a and 5a receptors and to rat and human brain sections[J]. J Neurochem,2000,75(6):2590-2601.
[11]Hathaway HA, Pshenichkin S, Grajkowska E,Gelb T,Emery AC,Wolfe BB,et al. Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism[J]. Neuropharmacology,2015,93:199-208.
[12]Christopoulos A,Kenakin T. G protein-coupled receptor allosterism and complexing[J]. Pharmacol Rev,2002,54(2):323-374.
[13]Leach K,Sexton PM,Christopoulos A. Allosteric GPCR modulators:taking advantage of permissive receptor pharmacology[J]. Trends Pharmacol Sci,2007,28(8):382-389.
[14]Bian Y,Feng Z,Yang P,Xie XQ. Integrated in silico fragment-based drug design:case study with allosteric modulators on metabotropic glutamate receptor 5[J]. AAPS J,2017,19(4):1235-1248.
[15]Gregory KJ,Herman EJ,Ramsey AJ,Hammond AS,Byun NE,Stauffer SR,et al. N-aryl piperazine metabotropic glutamate receptor 5 positive al osteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement[J]. J Pharmacol Exp Ther,2013,347(2):438-457.
[16]Rook JM,Noetzel MJ,Pouliot WA,Bridges TM,Vinson PN, Cho HP, et al. Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity[J]. Biol Psychiatry,2013,73(6):501-509.
[17]Fu T,Zheng G,Tu G,Yang,Chen Y,Yao X,et al.Exploring the binding mechanism of metabotropic glutamate receptor 5 negative al osteric modulators in clinical trials by molecular dynamics simulations[J]. ACS Chem Neurosci,2018,9(6):1492-1502.
[18]Bridges TM,Rook JM,Noetzel MJ,Morrison RD,Zhou Y,Gogliotti RD,et al. Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonismdependent mechanism[J]. Drug Metab Dispos,2013,41(9):1703-1714.
[19]Gregory KJ,Nguyen ED,Reiff SD,Squire EF,Stauffer SR, Lindsley CW, et al. Probing the metabotropic glutamate receptor 5(mGluR5)positive allosteric modulator(PAM)binding pocket:discovery of point mutations that engender a″molecular switch″in PAM pharmacology[J]. Mol Pharmacol,2013,83(5):991-1006.
[20]Parmentier-Batteur S, Hutson PH, Menzel K,Uslaner JM,Mattson BA,O′Brien JA,et al. Mechanism based neurotoxicity of m Glu5 positive al osteric modulators-psychotic target[J]. Neuropharmacology,2014,82:161-173.
[21]Gregory KJ, Conn PJ. Molecular insights into metabotropic glutamate receptor al osteric modulation[J]. Mol Pharmacol,2015,88(1):188-202.
[22]Watterson LR,Kufahl PR,Nemirovsky NE,Sewalia K,Hood LE,Olive MF. Attenuation of reinstatement of methamphetamine-,sucrose-,and food-seeking behavior in rats by fenobam,a metabotropic glutamate receptor 5 negative allosteric modulator[J].Psychopharmacology(Berl),2013,225(1):151-159.
[23]Hagerman RJ,Leehey M,Heinrichs W,Tassone F,Wilson R,Hills J,et al. Intention tremor,parkinsonism,and generalized brain atrophy in male carriers of fragile X[J]. Neurology,2001,57(1):127-130.
[24]Berry-Kravis EM,Lindemann L,J?nch AE,Apostol G,Bear MF,Carpenter RL,et al. Drug development for neurodevelopmental disorders:lessons learned from fragile X syndrome[J]. Nat Rev Drug Discov,2018,17(4):280-299.
[25]Pop AS,Gomez-Mancil a B,Neri G,Wil emsen R,Gasparini F. Fragile X syndrome:a preclinical review on metabotropic glutamate receptor 5(mGluR5)antagonists and drug development[J]. Psychopharmacology(Berl),2014,231(6):1217-1226.
[26]Guo W,Molinaro G,Colins KA,Hays SA,Paylor R,Worley PF,et al. Selective disruption of metabotropic glutamate receptor 5-Homer interactions mimics phenotypes of fragile X syndrome in mice[J]. J Neurosci,2016,36(7):2131-2147.
[27]Davenport MH, Schaefer TL, Friedmann KJ,Fitzpatrick SE,Erickson CA. Pharmacotherapy for Fragile X syndrome:progress to date[J]. Drugs,2016,76(4):431-445.
[28]Mattson MP,Furukawa K. Signaling events regulating the neurodevelopmental triad. Glutamate and secreted forms of beta-amyloid precursor protein as examples[J]. Perspect Dev Neurobiol,1998,5(4):337-352.
[29]Auerbach BD,Bear MF. Loss of the fragile X mental retardation protein decouples metabotropic glutamate receptor dependent priming of long-term potentiation from protein synthesis[J]. J Neurophysiol,2010,104(2):1047-1051.
[30]Li SH,Li XJ. Huntingtin-protein interactions and the pathogenesis of Huntington′s disease[J].Trends Genet,2004,20(3):146-154.
[31]Tang TS,Slow E,Lupu V,Stavrovskaya IG,Sugimori M,Llinás R,et al. Disturbed Ca2+signaling and apoptosis of medium spiny neurons in Huntington′s disease[J]. Proc Natl Acad Sci USA,2005,102(7):2602-2607.
[32]Ribeiro FM,Paquet M,Ferreira LT,Cregan T,Swan P,Cregan SP,et al. Metabotropic glutamate receptor-mediated cel signaling pathways are altered in a mouse model of Huntington′s disease[J]. J Neurosci,2010,30(1):316-324.
[33]Rong R,Ahn JY,Huang H,Nagata E,Kalman D,Kapp JA,et al. PI3 kinase enhancer-Homer complex couples m Glu RI to PI3 kinase,preventing neuronal apoptosis[J]. Nat Neurosci,2003,6(11):1153-1161.
[34]Doria JG,Silva FR,de Souza JM,Vieira LB,Carvalho TG,Reis HJ,et al. Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington′s disease[J]. Br J Pharmacol,2013,169(4):909-921.
[35]Lee M,Lee HJ,Park IS,Park JA,Kwon YJ,Ryu YH,et al. Aβpathology downregulates brain mGluR5 density in a mouse model of Alzheimer[J]. Neuropharmacology,2018,133:512-517.
[36]Ribeiro FM,Paquet M,Cregan SP,Ferguson SS.GroupⅠmetabotropic glutamate receptor signalling and its implication in neurological disease[J]. CNS Neurol Disord Drug Targets,2010,9(5):574-595.
[37]Kumar A,Dhul DK,Mishra PS. Therapeutic potential of m GluR5 targeting in Alzheimer′s disease[J/OL].Front Neurosci,2015,9:215(2015-06-09). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460345/
[38]Hamilton A,Esseltine JL,De Vries RA,Cregan SP,Ferguson SS. Metabotropic glutamate receptor 5knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer′s disease[J/OL]. Mol Brain,2014,7:40(2014-05-29). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050478/
[39]Um JW,Kaufman AC,Kostylev M,Heiss JK,Stagi M,Takahashi H,et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβoligomer bound to cel ular prion protein[J]. Neuron,2013,79(5):887-902.
[40]Goetz CG. The history of Parkinson′s disease:early clinical descriptions and neurological therapies[J/OL].Cold Spring Harb Perspect Med,2011,1(1):a008862(2011-09). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234454/
[41]Rascol O, Fox S, Gasparini F, Kenney C,Di Paolo T,Gomez-Mancilla B. Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias[J]. Parkinsonism Relat Disord,2014,20(9):947-956.
[42]Morin N,Morissette M,Grégoire L,Di Paolo T.mGlu5,Dopamine D2 and adenosine A2A receptors in L-DOPA-induced dyskinesias[J]. Curr Neuropharmacol,2016,14(5):481-493.
[43]Bezard E,Pioli EY,Li Q, Girard F, Mutel V,Keywood C,et al. The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model[J]. Mov Disord,2014,29(8):1074-1079.
[44]Melancon BJ,Tarr JC,Panarese JD,Wood MR,Lindsley CW. Allosteric modulation of the M1muscarinic acetylcholine receptor:improving cognition and a potential treatment for schizophrenia and Alzheimer′s disease[J]. Drug Discov Today,2013,18(23-24):1185-1199.
[45]Yang YS,Marder SR,Green MF. Repurposing drugs for cognition in schizophrenia[J]. Clin Pharmacol Ther,2017,101(2):191-193.
[46]Attucci S,CarlàV,Mannaioni G,Moroni F. Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges[J]. Br J Pharmacol,2001,132(4):799-806.
[47]O′Brien JA,Lemaire W,Wittmann M,Jacobson MA,Ha SN,Wisnoski DD,et al. A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain[J]. J Pharmacol Exp Ther,2004,309(2):568-577.
[48]Koob GF,Volkow ND. Neurocircuitry of addiction[J]. Neuropsychopharmacology,2010,35(1):217-238.
[49]Bj?rklund A,Dunnett SB. Dopamine neuron systems in the brain:an update[J]. Trends Neurosci,2007,30(5):194-202.
[50]Kalivas PW. The glutamate homeostasis hypothesis of addiction[J]. Nat Rev Neurosci,2009,10(8):561-572.
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