桥尾蛋白的结构、功能及其与神经系统疾病关系的研究进展
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摘要
桥尾蛋白(gephyrin)是第一个被发现的抑制性突触后膜骨架蛋白,也是中枢神经系统抑制性突触的突触后蛋白网络的重要组成部分。近年研究表明,桥尾蛋白在抑制性突触形成、稳定抑制性突触后膜受体、调节突触可塑性方面具有重要作用,桥尾蛋白异常可能与钼辅因子(MoCo)缺乏症、阿尔茨海默病(AD)、癫痫等神经系统疾病有关。本文综述了桥尾蛋白的结构、功能及其与神经系统疾病的关系,以期为早期预防、干预甚至治愈相关神经系统疾病提供参考。
Gephyrin,as the first founded inhibitory postsynaptic skeletal protein,is an important component of postsynaptic protein network of inhibitory synapse in central nervous system. In recent years,many studies showed that,gephyrin plays an important role in formation of inhibitory synapse,stabilization of inhibitory synaptic receptors and adjustment of synaptic plasticity,abnormality of gephyrin may correlated some nervous system disease,such as molybdenum cofactor deficiency,Alzheimer's disease and epilepsy. This paper mainly reviewed the structure,function of gephyrin and its relation with nervous system disease,to provide a reference for early prevention,intervention and even cure of nervous system disease.
Gephyrin,as the first founded inhibitory postsynaptic skeletal protein,is an important component of postsynaptic protein network of inhibitory synapse in central nervous system. In recent years,many studies showed that,gephyrin plays an important role in formation of inhibitory synapse,stabilization of inhibitory synaptic receptors and adjustment of synaptic plasticity,abnormality of gephyrin may correlated some nervous system disease,such as molybdenum cofactor deficiency,Alzheimer's disease and epilepsy. This paper mainly reviewed the structure,function of gephyrin and its relation with nervous system disease,to provide a reference for early prevention,intervention and even cure of nervous system disease.
引文
[1]ALVAREZ F J.Gephyrin and the regulation of synaptic strength and dynamics at glycinergic inhibitory synapses[J].Brain Res Bull,2016,129:50-65.DOI:10.1016/j.brainresbull.2016.09.003.
[2]JACOB T C,MOSS S J,JURD R.GABA(A)receptor trafficking and its role in the dynamic modulation of neuronal inhibition[J].Nat Rev Neurosci,2008,9(5):331-343.DOI:10.1038/nrn2370.
[3]NAWROTZKI R,ISLINGER M,VOGEL I,et al.Expression and subcellular distribution of gephyrin in non-neuronal tissues and cells[J].Histochem Cell Biol,2012,137(4):471-482.DOI:10.1007/s00418-012-0914-7.
[4]ZACCHI P,ANTONELLI R,CHERUBINI E.Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses[J].Front Cell Neurosci,2014,8(8):103.DOI:10.3389/fncel.2014.00103.
[5]DANIEL C,ANTOINE T.The dynamic synapse[J].Neuron,2013,80(3):691-703.DOI:10.1016/j.neuron.2013.10.013.
[6]COSTA J T,MELE M,BAPTISTA M S,et al.Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death[J].Mol Neurobiol,2016,53(6):3513-3527.DOI:10.1007/s12035-015-9283-2.
[7]BELAIDI A A,SCHWARZ G.Metal insertion into the molybdenum cofactor:product-substrate channelling demonstrates the functional origin of domain fusion in gephyrin[J].Biochemical Journal,2013,450(1):149-157.DOI:10.1042/BJ20121078.
[8]CALAMAI M,SPECHT C G,HELLER J,et al.Gephyrin oligomerization controls Gly R mobility and synaptic clustering[J].J Neurosci,2009,29(24):7639-7648.DOI:10.1523/JNEUROSCI.5711-08.2009.
[9]CHOII G,KO J.Gephyrin:a central GABAergic synapse organizer[J].Exp Mol Med,2015,47(3):e158.DOI:10.1038/emm.2015.5.
[10]TRETTER V,MUKHERJEE J,MARIC H M,et al.Gephyrin,the enigmatic organizer at GABAergic synapses[J].Front Cell Neurosci,2012,6(23):23.DOI:10.3389/fncel.2012.00023.
[11]SASSOè-POGNETTO M,PANZANELLI P,SIEGHART W,et al.Colocalization of multiple GABA(A)receptor subtypes with gephyrin at postsynaptic sites[J].J Comp Neurol,2000,420(4):481-498.
[12]LARDI-STUDLER B,SMOLINSKY B,PETITJEAN C M,et al.Vertebratespecific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering[J].J Cell Sci,2007,120(8):1371-1382.DOI:10.1242/jcs.003905.
[13]FRITSCHY J M,HARVEY R J,SCHWARZ G.Gephyrin:where do we stand,where do we go?[J].Trends Neurosci,2008,31(5):257-264.DOI:10.1016/j.tins.2008.02.006.
[14]TYAGARAJAN S K,FRITSCHY J M.Gephyrin:a master regulator of neuronal function?[J].Nat Rev Neurosci,2014,15(3):141-156.DOI:10.1038/nrn3670.
[15]LI B,WANKA L,BLANCHARD J,et al.Neurotrophic peptides incorporating adamantane improve learning and memory,promote neurogenesis and synaptic plasticity in mice[J].FEBS Lett,2010,584(15):3359-3365.DOI:10.1016/j.febslet.2010.06.025.
[16]PETRINI E M,RAVASENGA T,HAUSRAT T J,et al.Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP[J].Nat Commun,2014,5(6):3921-3940.DOI:10.1038/ncomms4921.
[17]MENDEL R R,SCHWARZ G.Molybdenum cofactor biosynthesis in plants and humans[J].Coordination Chemistry Reviews,2011,255(9):1145-1158.DOI:10.1016/j.ccr.2011.01.054.
[18]SRIVASTAVA S,PATHAK M,PANDEY H,et al.Molecular characterization of novel immunodominant molybdenum cofactor biosynthesis protein C1(Rv3111)from Mycobacterium tuberculosis H37Rv[J].Biochim Biophys Acta,2016,1860(4):694-707.DOI:10.1016/j.bbagen.2016.01.004.
[19]MENDEL R R,KRUSE T.Cell biology of molybdenum in plants and humans[J].Biochim Biophys Acta,2012,1823(9):1568-1579.DOI:10.1016/j.bbamcr.2012.02.007.
[20]ATWAL P S,SCAGLIA F.Molybdenum cofactor deficiency[J].Mol Genet Metab,2016,117(1):1-4.DOI:10.1016/j.ymgme.2015.11.010.
[21]SCHWARZ G,MENDEL R R,RIBBE M W.Molybdenum cofactors,enzymes and pathways[J].Nature,2009,460(7257):839-847.DOI:10.1038/nature08302.
[22]NAGAPPA M,BINDU P S,TALY A B,et al.Child Neurology:Molybdenum cofactor deficiency[J].Neurology,2015,85(23):e175-178.DOI:10.1212/wnl.0000000000002194.
[23]LEIMKüHLER S,IOBBI-NIVOL C.Bacterial molybdoenzymes:old enzymes for new purposes[J].FEMS Microbiol Rev,2016,40(1):1-18.DOI:10.1093/femsre/fuv043.
[24]DEJANOVIC B,DJéMIéT,GRüNEWALD N,et al.Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy[J].EMBO Mol Med,2015,7(12):1580-1594.DOI:10.15252/emmm.201505323.
[25]REISS J,HAHNEWALD R.Molybdenum cofactor deficiency:Mutations in GPHN,MOCS1,and MOCS2[J].Hum Mutat,2011,32(1):10-18.DOI:10.1002/humu.21390.
[26]REISS J,LENZ U,AQUAVIVA-BOURDAIN C,et al.A GPHNpoint mutation leading to molybdenum cofactor deficiency[J].Clin Genet,2011,80(6):598-599.DOI:10.1111/j.1399-0004.2011.01709.x.
[27]MUCKE L,SELKOE D J.Neurotoxicity of amyloidβ-protein:synaptic and network dysfunction[J].Cold Spring Harb Perspect in Med,2012,2(7):a006338.DOI:10.1101/cshperspect.a006338.
[28]VIOLA K L,KLEIN W L.Amyloidβoligomers in Alzheimer's disease pathogenesis,treatment,and diagnosis[J].Acta Neuropathol,2015,129(2):183-206.DOI:10.1007/s00401-015-1386-3.
[29]TU S,OKAMOTO S I,LIPTON S A,et al.Oligomeric Aβ-induced synaptic dysfunction in Alzheimer's disease[J].Mol Neurodegener,2014,9(1):48.DOI:10.1186/1750-1326-9-48.
[30]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(9):2279-2291.DOI:10.1016/j.ajpath.2016.05.013.
[31]HALES C M,REES H,SEYFRIED N T,et al.Abnormal gephyrin immunoreactivity associated with Alzheimer disease pathologic changes[J].J Neuropathol Exp Neurol,2013,72(11):1009-1015.DOI:10.1097/01.jnen.0000435847.59828.db.
[32]AGARWAL S,TANNENBERG R K,DODD P R.Reduced expression of the inhibitory synapse scaffolding protein gephyrin in Alzheimer's disease[J].J Alzheimers Dis,2008,14(3):313-321.DOI:10.3233/jad-2008-14305.
[33]GONZáLEZ M I.The possible role of GABAA receptors and gephyrin in epileptogenesis[J].Front Cell Neurosci,2013,7(7):113.DOI:10.3389/fncel.2013.00113.
[34]FANG M,SHEN L,YIN H,et al.Downregulation of gephyrin in temporal lobe epilepsy neurons in humans and a rat model[J].Synapse,2011,65(10):1006-1014.DOI:10.1002/syn.20928.
[35]SCHWARTZKROIN P A.Cellular bases of focal and generalized epilepsies[J].Handb Clin Neurol,2012,107:13-33.DOI:10.1016/B978-0-444-52898-8.00002-1.
[36]LIONEL A C,VAAGS A K,SATO D,et al.Rare exonic deletions implicate the synaptic organizer Gephyrin(GPHN)in risk for autism,schizophrenia and seizures[J].Hum Mol Genet,2013,22(10):2055-2066.DOI:10.1093/hmg/ddt056.
[37]F?RSTERA B,BELAIDI A A,JüTTNER R,et al.Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy[J].Brain,2010,133(12):3778-3794.DOI:10.1093/brain/awq298.
[38]KUMAR S S,BUCKMASTER P S.Hyperexcitability,interneurons,and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy[J].J Neurosci,2006,26(17):4613-4623.DOI:10.1523/jneurosci.0064-06.2006.
[2]JACOB T C,MOSS S J,JURD R.GABA(A)receptor trafficking and its role in the dynamic modulation of neuronal inhibition[J].Nat Rev Neurosci,2008,9(5):331-343.DOI:10.1038/nrn2370.
[3]NAWROTZKI R,ISLINGER M,VOGEL I,et al.Expression and subcellular distribution of gephyrin in non-neuronal tissues and cells[J].Histochem Cell Biol,2012,137(4):471-482.DOI:10.1007/s00418-012-0914-7.
[4]ZACCHI P,ANTONELLI R,CHERUBINI E.Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses[J].Front Cell Neurosci,2014,8(8):103.DOI:10.3389/fncel.2014.00103.
[5]DANIEL C,ANTOINE T.The dynamic synapse[J].Neuron,2013,80(3):691-703.DOI:10.1016/j.neuron.2013.10.013.
[6]COSTA J T,MELE M,BAPTISTA M S,et al.Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death[J].Mol Neurobiol,2016,53(6):3513-3527.DOI:10.1007/s12035-015-9283-2.
[7]BELAIDI A A,SCHWARZ G.Metal insertion into the molybdenum cofactor:product-substrate channelling demonstrates the functional origin of domain fusion in gephyrin[J].Biochemical Journal,2013,450(1):149-157.DOI:10.1042/BJ20121078.
[8]CALAMAI M,SPECHT C G,HELLER J,et al.Gephyrin oligomerization controls Gly R mobility and synaptic clustering[J].J Neurosci,2009,29(24):7639-7648.DOI:10.1523/JNEUROSCI.5711-08.2009.
[9]CHOII G,KO J.Gephyrin:a central GABAergic synapse organizer[J].Exp Mol Med,2015,47(3):e158.DOI:10.1038/emm.2015.5.
[10]TRETTER V,MUKHERJEE J,MARIC H M,et al.Gephyrin,the enigmatic organizer at GABAergic synapses[J].Front Cell Neurosci,2012,6(23):23.DOI:10.3389/fncel.2012.00023.
[11]SASSOè-POGNETTO M,PANZANELLI P,SIEGHART W,et al.Colocalization of multiple GABA(A)receptor subtypes with gephyrin at postsynaptic sites[J].J Comp Neurol,2000,420(4):481-498.
[12]LARDI-STUDLER B,SMOLINSKY B,PETITJEAN C M,et al.Vertebratespecific sequences in the gephyrin E-domain regulate cytosolic aggregation and postsynaptic clustering[J].J Cell Sci,2007,120(8):1371-1382.DOI:10.1242/jcs.003905.
[13]FRITSCHY J M,HARVEY R J,SCHWARZ G.Gephyrin:where do we stand,where do we go?[J].Trends Neurosci,2008,31(5):257-264.DOI:10.1016/j.tins.2008.02.006.
[14]TYAGARAJAN S K,FRITSCHY J M.Gephyrin:a master regulator of neuronal function?[J].Nat Rev Neurosci,2014,15(3):141-156.DOI:10.1038/nrn3670.
[15]LI B,WANKA L,BLANCHARD J,et al.Neurotrophic peptides incorporating adamantane improve learning and memory,promote neurogenesis and synaptic plasticity in mice[J].FEBS Lett,2010,584(15):3359-3365.DOI:10.1016/j.febslet.2010.06.025.
[16]PETRINI E M,RAVASENGA T,HAUSRAT T J,et al.Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP[J].Nat Commun,2014,5(6):3921-3940.DOI:10.1038/ncomms4921.
[17]MENDEL R R,SCHWARZ G.Molybdenum cofactor biosynthesis in plants and humans[J].Coordination Chemistry Reviews,2011,255(9):1145-1158.DOI:10.1016/j.ccr.2011.01.054.
[18]SRIVASTAVA S,PATHAK M,PANDEY H,et al.Molecular characterization of novel immunodominant molybdenum cofactor biosynthesis protein C1(Rv3111)from Mycobacterium tuberculosis H37Rv[J].Biochim Biophys Acta,2016,1860(4):694-707.DOI:10.1016/j.bbagen.2016.01.004.
[19]MENDEL R R,KRUSE T.Cell biology of molybdenum in plants and humans[J].Biochim Biophys Acta,2012,1823(9):1568-1579.DOI:10.1016/j.bbamcr.2012.02.007.
[20]ATWAL P S,SCAGLIA F.Molybdenum cofactor deficiency[J].Mol Genet Metab,2016,117(1):1-4.DOI:10.1016/j.ymgme.2015.11.010.
[21]SCHWARZ G,MENDEL R R,RIBBE M W.Molybdenum cofactors,enzymes and pathways[J].Nature,2009,460(7257):839-847.DOI:10.1038/nature08302.
[22]NAGAPPA M,BINDU P S,TALY A B,et al.Child Neurology:Molybdenum cofactor deficiency[J].Neurology,2015,85(23):e175-178.DOI:10.1212/wnl.0000000000002194.
[23]LEIMKüHLER S,IOBBI-NIVOL C.Bacterial molybdoenzymes:old enzymes for new purposes[J].FEMS Microbiol Rev,2016,40(1):1-18.DOI:10.1093/femsre/fuv043.
[24]DEJANOVIC B,DJéMIéT,GRüNEWALD N,et al.Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy[J].EMBO Mol Med,2015,7(12):1580-1594.DOI:10.15252/emmm.201505323.
[25]REISS J,HAHNEWALD R.Molybdenum cofactor deficiency:Mutations in GPHN,MOCS1,and MOCS2[J].Hum Mutat,2011,32(1):10-18.DOI:10.1002/humu.21390.
[26]REISS J,LENZ U,AQUAVIVA-BOURDAIN C,et al.A GPHNpoint mutation leading to molybdenum cofactor deficiency[J].Clin Genet,2011,80(6):598-599.DOI:10.1111/j.1399-0004.2011.01709.x.
[27]MUCKE L,SELKOE D J.Neurotoxicity of amyloidβ-protein:synaptic and network dysfunction[J].Cold Spring Harb Perspect in Med,2012,2(7):a006338.DOI:10.1101/cshperspect.a006338.
[28]VIOLA K L,KLEIN W L.Amyloidβoligomers in Alzheimer's disease pathogenesis,treatment,and diagnosis[J].Acta Neuropathol,2015,129(2):183-206.DOI:10.1007/s00401-015-1386-3.
[29]TU S,OKAMOTO S I,LIPTON S A,et al.Oligomeric Aβ-induced synaptic dysfunction in Alzheimer's disease[J].Mol Neurodegener,2014,9(1):48.DOI:10.1186/1750-1326-9-48.
[30]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(9):2279-2291.DOI:10.1016/j.ajpath.2016.05.013.
[31]HALES C M,REES H,SEYFRIED N T,et al.Abnormal gephyrin immunoreactivity associated with Alzheimer disease pathologic changes[J].J Neuropathol Exp Neurol,2013,72(11):1009-1015.DOI:10.1097/01.jnen.0000435847.59828.db.
[32]AGARWAL S,TANNENBERG R K,DODD P R.Reduced expression of the inhibitory synapse scaffolding protein gephyrin in Alzheimer's disease[J].J Alzheimers Dis,2008,14(3):313-321.DOI:10.3233/jad-2008-14305.
[33]GONZáLEZ M I.The possible role of GABAA receptors and gephyrin in epileptogenesis[J].Front Cell Neurosci,2013,7(7):113.DOI:10.3389/fncel.2013.00113.
[34]FANG M,SHEN L,YIN H,et al.Downregulation of gephyrin in temporal lobe epilepsy neurons in humans and a rat model[J].Synapse,2011,65(10):1006-1014.DOI:10.1002/syn.20928.
[35]SCHWARTZKROIN P A.Cellular bases of focal and generalized epilepsies[J].Handb Clin Neurol,2012,107:13-33.DOI:10.1016/B978-0-444-52898-8.00002-1.
[36]LIONEL A C,VAAGS A K,SATO D,et al.Rare exonic deletions implicate the synaptic organizer Gephyrin(GPHN)in risk for autism,schizophrenia and seizures[J].Hum Mol Genet,2013,22(10):2055-2066.DOI:10.1093/hmg/ddt056.
[37]F?RSTERA B,BELAIDI A A,JüTTNER R,et al.Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy[J].Brain,2010,133(12):3778-3794.DOI:10.1093/brain/awq298.
[38]KUMAR S S,BUCKMASTER P S.Hyperexcitability,interneurons,and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy[J].J Neurosci,2006,26(17):4613-4623.DOI:10.1523/jneurosci.0064-06.2006.