title: Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2.
abstract: The activity-regulated cytoskeleton-associated (Arc) protein controls synaptic strength by facilitating AMPA receptor (AMPAR) endocytosis. Here we demonstrate that Arc targets AMPAR to be internalized through a direct interaction with the clathrin-adaptor protein 2 (AP-2). We show that Arc overexpression in dissociated hippocampal neurons obtained from C57BL/6 mouse reduces the density of AMPAR GluA1 subunits at the cell surface and reduces the amplitude and rectification of AMPAR-mediated miniature-EPSCs (mEPSCs). Mutations of Arc, that prevent the AP-2 interaction reduce Arc-mediated endocytosis of GluA1 and abolish the reduction in AMPAR-mediated mEPSC amplitude and rectification. Depletion of the AP-2 subunit µ2 blocks the Arc-mediated reduction in mEPSC amplitude, an effect that is restored by reintroducing µ2. The Arc-AP-2 interaction plays an important role in homeostatic synaptic scaling as the Arc-dependent decrease in mEPSC amplitude, induced by a chronic increase in neuronal activity, is inhibited by AP-2 depletion. These data provide a mechanism to explain how activity-dependent expression of Arc decisively controls the fate of AMPAR at the cell surface and modulates synaptic strength, via the direct interaction with the endocytic clathrin adaptor AP-2.
authors.affiliation: Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto, São Paulo, 14049-900 Brazil.
authors.forename: Luis L P
authors.identifier: 0000-0003-3558-0087
authors.initials: LL
authors.lastname: DaSilva
authors.affiliation: School of Life Sciences, University of Warwick , Coventry, CV4 7AL United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Wall
authors.affiliation: Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900 Brazil; Bradford School of Pharmacy, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, United Kingdom.
authors.forename: Luciana
authors.initials: L
authors.lastname: P de Almeida
authors.affiliation: School of Life Sciences, University of Warwick , Coventry, CV4 7AL United Kingdom.
authors.forename: Sandrine C
authors.initials: SC
authors.lastname: Wauters
authors.affiliation: Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto, São Paulo, 14049-900 Brazil.
authors.forename: Yunan C
authors.initials: YC
authors.lastname: Januário
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, CV4 7AL United Kingdom; Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham B4 7ET, United Kingdom.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Müller
authors.affiliation: School of Life Sciences, University of Warwick, Coventry, CV4 7AL United Kingdom; Bradford School of Pharmacy, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, United Kingdom.
authors.forename: Sonia A L
authors.identifier: 0000-0002-7434-1073
authors.initials: SA
authors.lastname: Corrêa
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D004926:Escherichia coli; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020543:Proteome; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D033962:Adaptor Protein Complex 2; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D020543:Proteome; D018091:Receptors, AMPA; D011994:Recombinant Proteins; C092069:activity regulated cytoskeletal-associated protein
keywords: : adaptor protein 2; AMPAR endocytosis; clathrin-mediated endocytosis; hippocampus; neuronal excitability; synaptic transmission