Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptor-associated PDZ proteins in developing cortical neurons

摘要

PostsynapticmoleculeswithPDZdomains(PDZproteins)interactwithvariousglutamatereceptorsandregulatetheirsubcellulartraffickingandstability.Inratneocorticaldevelopment,theproteinexpressionofAMPA-typeglutamatereceptorGluR1laggedbehinditsmRNAexpressionandratherparalleledanincreaseinPDZproteinlevels.Oneoftheneurotrophins,brain-derivedneurotrophicfactor(BDNF),appearedtocontributetothisprocess,regulatingthePDZproteinexpression.Inneocorticalcultures,BDNFtreatmentupregulatedSAP97,GRIP1,andPick1PDZproteins.Conversely,BDNFgenetargetingdownregulatedthesesamePDZmolecules.TheBDNF-triggeredincreasesinPDZproteinsresultedintheelevationoftheirtotalassociationwiththeAMPAreceptorsGluR1andGluR2/3,whichledtotheincreaseinAMPAreceptorproteins.WhenSindbisvirusescarryingGluR1orGluR2C-terminaldecoysdisruptedtheirinteractions,GluR2C-terminaldecoysinhibitedbothBDNF-triggeredGluR1andGluR2/3increases,whereasGluR1C-terminaldecoysblockedonlytheBDNF-triggeredGluR1increase.Inagreement,coexpressionofSAP97andGluR1innonneuronalHEK293cellsincreasedbothproteinscomparedwiththeirsingletransfection,implyingmutualstabilization.ThisworkrevealsanovelfunctionofBDNFinpostsynapticdevelopmentbyregulatingthePDZproteinexpression./p/div