Gephyrin:抑制性突触后蛋白网络的核心骨架蛋白
摘要
Gephyrin是中枢神经系统(CNS)抑制性突触后蛋白网络的核心骨架蛋白,具有参与抑制性突触形成、稳定抑制性突触受体、调节突触可塑性等作用。Gephyrin翻译后修饰对Gephyrin功能的正常发挥具有重要调节作用。Gephyrin结构和功能异常与癫痫、精神分裂症等多种神经精神疾病的发生有关。
引文
[1]Alvarez FJ.Gephyrin and the regulation of synaptic strength and dynamic at glycinergicinhibitory synapses[J].Brain Res Bull,2017,129:50-65.
[2]Kuhse J,Kalbouneh H,Schlicksupp A,et al.Phosphorylation of gephyrin in hippocampal neurons by cyclin dependent kinase CDK5 at Ser-270 is dependent on collybistin[J].J Biol Chem,2012,287:30952-30966.
[3]Pfeiffer F,Graham D,Betz H.Purification by affinity chromatography of the glycine receptor of rat spinal cord[J].J Biol Chem,1982,257:9389-9393.
[4]Prior P,Schmitt B,Grenningloh G,et al.Primary structure and alternative splice variants of gephyrin,a putative glycine receptor-tubulin linker protein[J].Neuron,1992,8:1161-1170.
[5]Maas C,Belgardt D,Lee HK,et al.Synaptic activation modifies microtubules underlying transport of postsynaptic cargo[J].Proc Natl Acad Sci USA,2009,16:8731-8736.
[6]Kasaragod VB,Schindelin H.Structural Framework for Metal Incorporation during Molybdenum Cofactor Biosynthesis[J].Structure,2016,24:782-788.
[7]Reiss J,Lenz U,Aquaviva-Bourdain C,et al.A GPHN point mutation leading to molybdenum cofactor deficiency[J].Clin Genet,2011,80:598-599.
[8]Lardi-Studler B,Smolinsky B,Petitjean CM,et al.Vertebrate-specific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering[J].J Cell Biol,2007,120:1371-1382.
[9]Specht CG,Izeddin I,Rodriguez PC,et al.Quantitative Nanoscopy of Inhibitory Synapses:Counting Gephyrin Molecules and Receptor Binding Sites[J].Neuron,2013,79:308-321.
[10]Fischer F,Kneussel M,Tintrup H,et al.Reduced synaptic clustering of GABA and glycine receptors in the retina of the gephyrin null mutant mouse[J].J Comp Neurol,2000,427:634-648.
[11]Meyer G,Kirsch J,Betz H,et al.Identification of a gephyrin binding motif on the glycine receptor subunit[J].Neuron,1995,15:563-572.
[12]Günther U,Benson J,Benke D,et al.Benzodiazepine-insensitive mice generated by targeted disruption of the 2-subunit gene ofaminobutyric acid type A receptors[J].Proc Natl Acad Sci USA,1995,92:7749-7753.
[13]Kralic JE,Sidler C,Parpan F,et al.Compensatory alteration of inhibitory synaptic circuits in thalamus and cerebellum of GABAAreceptor 1 subunit knockout mice[J].J Comp Neurol,2006,495:408-421.
[14]Peden DR,Petitjean CM,Herd MB,et al.Developmental maturation of synaptic and extrasynaptic GABAA receptors in mouse thalamic ventrobasal neurones[J].J Physiol,2008,586:965-987.
[15]Studer R,von Boehmer L,Haenggi T,et al.Alteration of GABAergic synapses and gephyrin clusters in the thalamic reticular nucleus of GABAA receptor 3 subunit-null mice[J].Eur J Neurosci,2006,24:1307-1315.
[16]Um JW,Choii G,Park D,et al.IQ Motif and SEC7 Domaincontaining Protein 3(IQSEC3)Interacts with Gephyrin to Promote Inhibitory Synapse Formation[J].J Biol Chem,2016,291:10119-10130.
[17]Pettem KL,Yokomaku D,Takahashi H,et al.Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development[J].J Cell Biol,2013,200:321-336.
[18]Tyagarajan SK,Ghosh H,Yévenes GE,et al.Regulation of GABAergic synapse formation and plasticity by GSK3-dependent phosphorylation of gephyrin[J].Proc Natl Acad Sci USA,2011,108:379-384.
[19]Kalbouneh H,Schlicksupp A,Kirsch J,et al.Cyclin-Dependent Kinase 5 Is Involved in the Phosphorylation of Gephyrin and Clustering of GABAA Receptors at Inhibitory Synapses of Hippocampal Neurons[J].PLoS ONE,2014,9:e104256.
[20]Frola E,Patrizi A,Goetz T,et al.Synaptic competition sculpts the development of GABAergic axodendritic but not perisomatic synapses[J].PLoS ONE,2013,8:e56311.
[21]Kirsch J,Betz H.Glycine-receptor activation is required for receptor clustering in spinal neurons[J].Nature,1998,392:717-720.
[22]Pennacchietti F,Vascon S,Nieus T,et al.Nanoscale Molecular Reorganization of the Inhibitory Postsynaptic Density Is a Determinant of GABAergic Synaptic Potentiation[J].J Neurosci,2017,37:1747-1756.
[23]Rui Y,Myers KR,Yu K,et al.Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3β[J].Nat Commun,2013,4:2628.
[24]Dejanovic B,Semtner M,Ebert S,et al.Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses[J].PLoS Biol,2014,12:e1001908.
[25]Lenz M,Galanis C,Muller-Dahlhaus F,et al.Repetitive magnetic stimulation induces plasticity of inhibitory synapses[J].Nat Commun,2016,7:10020.
[26]Pallotto M,Nissant A,Fritschy JM,et al.Early formation of GABAergic synapses governs the development of adult-born neurons in the olfactory bulb[J].J Neurosci,2012,32:9103-9115.
[27]Dejanovic B,Schwarz G.Neuronal Nitric Oxide Synthase-Dependent S-Nitrosylation of Gephyrin Regulates Gephyrin Clustering at GABAergic Synapses[J].J Neurosci,2014,34:7763-7768.
[28]Tyagarajan SK,Ghosh H,Yevenes GE,et al.Extracellular signalregulated kinase and glycogen synthase kinase 3beta regulate gephyrin postsynaptic aggregation and GABAergic synaptic function in a calpaindependent mechanism[J].J Biol Chem,2013,288:9634-9647.
[29]Zacchi P,Antonelli R,Cherubini E.Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses[J].Front Cell Neurosci,2014,8:103.
[30]Ghosh H,Auguadri L,Battaglia S,et al.Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission[J].Nat Commun,2016,7:13365.
[31]F?rstera B,Belaidi AA,Jüttner R,et al.Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy[J].Brain,2010,133:3778-3794.
[32]Mele M,Ribeiro L,Inácio AR,et al.GABA(A)receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia[J].Neurobiol Dis,2014,65:220-232.
[33]Kiss E,Gorgas K,Schlicksupp A,et al.Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model[J].Am J Pathol,2016,186:2279-2291.
[34]Al-Futaisi AM,Al-Kindi MN,Al-Mawali AM,et al.Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation[J].Pediatr Neurol,2012,46:89-93.
[35]Balan S,Yamada K,Iwayama Y,et al.Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia[J].Schizophr Res,2017,185:33-40.
[36]Isshiki M,Tanaka S,Kuriu T,et al.Enhanced synapse remodelling as a common phenotype in mouse models of autism[J].Nat Commun,2014,5:4742.
[37]Shen Q,Fuchs T,Sahir N,et al.GABAergic control of critical developmental periods for anxiety-and depression-related behavior in mice[J].PLoS ONE,2012,7:e47441.
[38]龚雪琴,罗利俊.血管性痴呆与阿尔茨海默病患者的认知功能及精神行为症状对比分析[J].神经损伤与功能重建,2017,12:122-123,127.
[39]Liang J,López-Valdés HE,Martínez-Coria H,et al.Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer’s disease[J].Neurochem Res,2014,39:1171-1181.
[2]Kuhse J,Kalbouneh H,Schlicksupp A,et al.Phosphorylation of gephyrin in hippocampal neurons by cyclin dependent kinase CDK5 at Ser-270 is dependent on collybistin[J].J Biol Chem,2012,287:30952-30966.
[3]Pfeiffer F,Graham D,Betz H.Purification by affinity chromatography of the glycine receptor of rat spinal cord[J].J Biol Chem,1982,257:9389-9393.
[4]Prior P,Schmitt B,Grenningloh G,et al.Primary structure and alternative splice variants of gephyrin,a putative glycine receptor-tubulin linker protein[J].Neuron,1992,8:1161-1170.
[5]Maas C,Belgardt D,Lee HK,et al.Synaptic activation modifies microtubules underlying transport of postsynaptic cargo[J].Proc Natl Acad Sci USA,2009,16:8731-8736.
[6]Kasaragod VB,Schindelin H.Structural Framework for Metal Incorporation during Molybdenum Cofactor Biosynthesis[J].Structure,2016,24:782-788.
[7]Reiss J,Lenz U,Aquaviva-Bourdain C,et al.A GPHN point mutation leading to molybdenum cofactor deficiency[J].Clin Genet,2011,80:598-599.
[8]Lardi-Studler B,Smolinsky B,Petitjean CM,et al.Vertebrate-specific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering[J].J Cell Biol,2007,120:1371-1382.
[9]Specht CG,Izeddin I,Rodriguez PC,et al.Quantitative Nanoscopy of Inhibitory Synapses:Counting Gephyrin Molecules and Receptor Binding Sites[J].Neuron,2013,79:308-321.
[10]Fischer F,Kneussel M,Tintrup H,et al.Reduced synaptic clustering of GABA and glycine receptors in the retina of the gephyrin null mutant mouse[J].J Comp Neurol,2000,427:634-648.
[11]Meyer G,Kirsch J,Betz H,et al.Identification of a gephyrin binding motif on the glycine receptor subunit[J].Neuron,1995,15:563-572.
[12]Günther U,Benson J,Benke D,et al.Benzodiazepine-insensitive mice generated by targeted disruption of the 2-subunit gene ofaminobutyric acid type A receptors[J].Proc Natl Acad Sci USA,1995,92:7749-7753.
[13]Kralic JE,Sidler C,Parpan F,et al.Compensatory alteration of inhibitory synaptic circuits in thalamus and cerebellum of GABAAreceptor 1 subunit knockout mice[J].J Comp Neurol,2006,495:408-421.
[14]Peden DR,Petitjean CM,Herd MB,et al.Developmental maturation of synaptic and extrasynaptic GABAA receptors in mouse thalamic ventrobasal neurones[J].J Physiol,2008,586:965-987.
[15]Studer R,von Boehmer L,Haenggi T,et al.Alteration of GABAergic synapses and gephyrin clusters in the thalamic reticular nucleus of GABAA receptor 3 subunit-null mice[J].Eur J Neurosci,2006,24:1307-1315.
[16]Um JW,Choii G,Park D,et al.IQ Motif and SEC7 Domaincontaining Protein 3(IQSEC3)Interacts with Gephyrin to Promote Inhibitory Synapse Formation[J].J Biol Chem,2016,291:10119-10130.
[17]Pettem KL,Yokomaku D,Takahashi H,et al.Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development[J].J Cell Biol,2013,200:321-336.
[18]Tyagarajan SK,Ghosh H,Yévenes GE,et al.Regulation of GABAergic synapse formation and plasticity by GSK3-dependent phosphorylation of gephyrin[J].Proc Natl Acad Sci USA,2011,108:379-384.
[19]Kalbouneh H,Schlicksupp A,Kirsch J,et al.Cyclin-Dependent Kinase 5 Is Involved in the Phosphorylation of Gephyrin and Clustering of GABAA Receptors at Inhibitory Synapses of Hippocampal Neurons[J].PLoS ONE,2014,9:e104256.
[20]Frola E,Patrizi A,Goetz T,et al.Synaptic competition sculpts the development of GABAergic axodendritic but not perisomatic synapses[J].PLoS ONE,2013,8:e56311.
[21]Kirsch J,Betz H.Glycine-receptor activation is required for receptor clustering in spinal neurons[J].Nature,1998,392:717-720.
[22]Pennacchietti F,Vascon S,Nieus T,et al.Nanoscale Molecular Reorganization of the Inhibitory Postsynaptic Density Is a Determinant of GABAergic Synaptic Potentiation[J].J Neurosci,2017,37:1747-1756.
[23]Rui Y,Myers KR,Yu K,et al.Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3β[J].Nat Commun,2013,4:2628.
[24]Dejanovic B,Semtner M,Ebert S,et al.Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses[J].PLoS Biol,2014,12:e1001908.
[25]Lenz M,Galanis C,Muller-Dahlhaus F,et al.Repetitive magnetic stimulation induces plasticity of inhibitory synapses[J].Nat Commun,2016,7:10020.
[26]Pallotto M,Nissant A,Fritschy JM,et al.Early formation of GABAergic synapses governs the development of adult-born neurons in the olfactory bulb[J].J Neurosci,2012,32:9103-9115.
[27]Dejanovic B,Schwarz G.Neuronal Nitric Oxide Synthase-Dependent S-Nitrosylation of Gephyrin Regulates Gephyrin Clustering at GABAergic Synapses[J].J Neurosci,2014,34:7763-7768.
[28]Tyagarajan SK,Ghosh H,Yevenes GE,et al.Extracellular signalregulated kinase and glycogen synthase kinase 3beta regulate gephyrin postsynaptic aggregation and GABAergic synaptic function in a calpaindependent mechanism[J].J Biol Chem,2013,288:9634-9647.
[29]Zacchi P,Antonelli R,Cherubini E.Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses[J].Front Cell Neurosci,2014,8:103.
[30]Ghosh H,Auguadri L,Battaglia S,et al.Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission[J].Nat Commun,2016,7:13365.
[31]F?rstera B,Belaidi AA,Jüttner R,et al.Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy[J].Brain,2010,133:3778-3794.
[32]Mele M,Ribeiro L,Inácio AR,et al.GABA(A)receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia[J].Neurobiol Dis,2014,65:220-232.
[33]Kiss E,Gorgas K,Schlicksupp A,et al.Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model[J].Am J Pathol,2016,186:2279-2291.
[34]Al-Futaisi AM,Al-Kindi MN,Al-Mawali AM,et al.Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation[J].Pediatr Neurol,2012,46:89-93.
[35]Balan S,Yamada K,Iwayama Y,et al.Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia[J].Schizophr Res,2017,185:33-40.
[36]Isshiki M,Tanaka S,Kuriu T,et al.Enhanced synapse remodelling as a common phenotype in mouse models of autism[J].Nat Commun,2014,5:4742.
[37]Shen Q,Fuchs T,Sahir N,et al.GABAergic control of critical developmental periods for anxiety-and depression-related behavior in mice[J].PLoS ONE,2012,7:e47441.
[38]龚雪琴,罗利俊.血管性痴呆与阿尔茨海默病患者的认知功能及精神行为症状对比分析[J].神经损伤与功能重建,2017,12:122-123,127.
[39]Liang J,López-Valdés HE,Martínez-Coria H,et al.Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer’s disease[J].Neurochem Res,2014,39:1171-1181.