title: Ubiquitin ligase RNF167 regulates AMPA receptor-mediated synaptic transmission.
abstract: AMPA receptors (AMPARs) mediate the majority of fast excitatory neurotransmission, and their density at postsynaptic sites determines synaptic strength. Ubiquitination is a posttranslational modification that dynamically regulates the synaptic expression of many proteins. However, very few of the ubiquitinating enzymes implicated in the process have been identified. In a screen to identify transmembrane RING domain-containing E3 ubiquitin ligases that regulate surface expression of AMPARs, we identified RNF167. Predominantly lysosomal, a subpopulation of RNF167 is located on the surface of cultured neurons. Using a RING mutant RNF167 or a specific shRNA to eliminate endogenous RNF167, we demonstrate that AMPAR surface expression increases in hippocampal neurons with disrupted RNF167 activity and that RNF167 is involved in activity-dependent ubiquitination of AMPARs. In addition, RNF167 regulates synaptic AMPAR currents, whereas synaptic NMDAR currents are unaffected. Therefore, our study identifies RNF167 as a selective regulator of AMPAR-mediated neurotransmission and expands our understanding of how ubiquitination dynamically regulates excitatory synapses.
authors.affiliation: Receptor Biology Section and Biochemistry Section/Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Lussier
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Herring
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nasu-Nishimura
authors.forename: Albert
authors.initials: A
authors.lastname: Neutzner
authors.forename: Mariusz
authors.initials: M
authors.lastname: Karbowski
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Roger A
authors.initials: RA
authors.lastname: Nicoll
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Roche
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D009435:Synaptic Transmission; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D012333:RNA, Messenger; D018091:Receptors, AMPA; D044767:Ubiquitin-Protein Ligases; C577769:RNF167 protein, rat; C108062:TTC3 protein, human; C104722:glutamate receptor ionotropic, AMPA 2