title: Porcupine Controls Hippocampal AMPAR Levels, Composition, and Synaptic Transmission.
abstract: AMPA receptor (AMPAR) complexes contain auxiliary subunits that modulate receptor trafficking and gating. In addition to the transmembrane AMPAR regulatory proteins (TARPs) and cornichons (CNIH-2/3), recent proteomic studies identified a diverse array of additional AMPAR-associated transmembrane and secreted partners. We systematically surveyed these and found that PORCN and ABHD6 increase GluA1 levels in transfected cells. Knockdown of PORCN in rat hippocampal neurons, which express it in high amounts, selectively reduces levels of all tested AMPAR complex components. Regulation of AMPARs is independent of PORCN's membrane-associated O-acyl transferase activity. PORCN knockdown in hippocampal neurons decreases AMPAR currents and accelerates desensitization and leads to depletion of TARP γ-8 from AMPAR complexes. Conditional PORCN knockout mice also exhibit specific changes in AMPAR expression and gating that reduce basal synaptic transmission but leave long-term potentiation intact. These studies define additional roles for PORCN in controlling synaptic transmission by regulating the level and composition of hippocampal AMPAR complexes.
authors.affiliation: Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA; Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Erlenhardt
authors.affiliation: Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Abiraman
authors.affiliation: CNNR program, Department of Cellular and Molecular Physiology, Yale University School of Medicine, 295 Congress Avenue BCMM441, P.O. Box 208026, New Haven, CT 06510, USA.
authors.forename: Tokiwa
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jacques I
authors.initials: JI
authors.lastname: Wadiche
authors.affiliation: CNNR program, Department of Cellular and Molecular Physiology, Yale University School of Medicine, 295 Congress Avenue BCMM441, P.O. Box 208026, New Haven, CT 06510, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tomita
authors.affiliation: Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA. Electronic address: dbredt@its.jnj.com.
authors.forename: David S
authors.initials: DS
authors.lastname: Bredt
mesh_terms: D000217:Acyltransferases; D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D017774:Long-Term Potentiation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission; D014981:Xenopus
chemical_list: D008565:Membrane Proteins; D009687:Nuclear Proteins; D018091:Receptors, AMPA; C413185:TARP; D000217:Acyltransferases; C491187:Porcn protein, mouse