title: Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders.
abstract: Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|Division of Oncology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.|iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita 565-0871, Japan.
authors.forename: Ryota
authors.identifier: http://orcid.org/0000-0002-5941-4238
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Sakoori
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugaya
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Tanimura
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hashimotodani
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohi
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.|Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Hidenaga
authors.initials: H
authors.lastname: Yamamori
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Umeda-Yano
authors.affiliation: Division of Neuronal Network, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kiyama
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Kohtarou
authors.initials: K
authors.lastname: Konno
authors.affiliation: Division of Oncology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Division of Oncology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yokoyama
authors.affiliation: Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Psychiatry, Course of Integrated Brain Sciences, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Numata
authors.affiliation: Department of Psychiatry, Juntendo University School of Medicine, Tokyo 113-0033, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohnuma
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.
authors.forename: Nakao
authors.identifier: http://orcid.org/0000-0003-3189-6076
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita 565-0871, Japan.|Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan.
authors.forename: Hitoshi
authors.identifier: http://orcid.org/0000-0001-6548-4016
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Division of Neuronal Network, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
authors.affiliation: Division of Oncology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.|Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son 904-0495, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita 565-0871, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020813:Receptor, trkB / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058305:Sorting Nexins / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000235:genetics* / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020690:GTPase-Activating Proteins; D012333:RNA, Messenger; D020813:Receptor, trkB; D058305:Sorting Nexins; D000099183:Sortilin; C475477:ARHGAP33 protein, human; C584832:SNX26 protein, mouse
references.citation: J Neurosci. 2011 May 25;31(21):7700-14
references.pmid: 21613483
references.citation: Nat Neurosci. 2011 Mar;14(3):285-93
references.pmid: 21346746
references.citation: J Hum Genet. 2011 Jul;56(7):478-83
references.pmid: 21512575
references.citation: PLoS One. 2011;6(7):e22716
references.pmid: 21818371
references.citation: Mol Cell Neurosci. 2011 Dec;48(4):278-87
references.pmid: 21762782
references.citation: Cold Spring Harb Perspect Biol. 2011 Dec;3(12). pii: a005678. doi: 10.1101/cshperspect.a005678
references.pmid: 22046028
references.citation: Neuroscience. 2011 Dec 29;199:589-97
references.pmid: 21964473
references.citation: Biochem J. 2012 Jan 1;441(1):39-59
references.pmid: 22168438
references.citation: PLoS One. 2012;7(1):e29780
references.pmid: 22253779
references.citation: Trends Neurosci. 2012 Apr;35(4):261-70
references.pmid: 22341525
references.citation: PLoS One. 2012;7(4):e35696
references.pmid: 22530067
references.citation: Trends Cell Biol. 2012 May;22(5):266-73
references.pmid: 22444728
references.citation: J Neurosci Res. 2012 Jul;90(7):1445-53
references.pmid: 22388794
references.citation: Neuroscience. 2012 Jun 14;212:1-18
references.pmid: 22542678
references.citation: Genome Biol. 2012;13(1):237
references.pmid: 22269335
references.citation: Genes Dev. 2012 Aug 1;26(15):1743-57
references.pmid: 22810622
references.citation: Immunity. 2012 Nov 16;37(5):854-66
references.pmid: 23084031
references.citation: Nat Rev Neurosci. 2013 Jan;14(1):7-23
references.pmid: 23254191
references.citation: Schizophr Bull. 2013 Jan;39(1):130-40
references.pmid: 21795612
references.citation: Nat Commun. 2013;4:1440
references.pmid: 23385585
references.citation: J Neurosci. 2013 Apr 3;33(14):6112-22
references.pmid: 23554492
references.citation: Nat Med. 2013 Apr;19(4):473-80
references.pmid: 23524343
references.citation: Nat Rev Neurosci. 2013 Jun;14(6):401-16
references.pmid: 23674053
references.citation: Am J Psychiatry. 2013 Jun;170(6):683-4
references.pmid: 23732972
references.citation: J Physiol. 2013 Oct 1;591(19):4765-76
references.pmid: 23858009
references.citation: J Biol Chem. 2013 Oct 11;288(41):29453-66
references.pmid: 24003235
references.citation: Schizophr Res. 2013 Dec;151(1-3):124-32
references.pmid: 24200419
references.citation: Nat Commun. 2014;5:3176
references.pmid: 24458027
references.citation: J Neurosci. 2014 Apr 23;34(17):5927-37
references.pmid: 24760852
references.citation: Transl Psychiatry. 2014;4:e389
references.pmid: 24802307
references.citation: Curr Opin Neurobiol. 2014 Aug;27:165-70
references.pmid: 24762653
references.citation: Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11840-5
references.pmid: 25071192
references.citation: Curr Pharm Des. 2014;20(31):5104-14
references.pmid: 24345269
references.citation: Int J Neuropsychopharmacol. 2015 Feb;18(4). pii: pyu077. doi: 10.1093/ijnp/pyu077
references.pmid: 25628381
references.citation: J Neurosci. 2015 Mar 11;35(10):4469-81
references.pmid: 25762688
references.citation: Curr Opin Genet Dev. 2011 Jun;21(3):340-8
references.pmid: 21376566
references.citation: Neuropsychopharmacology. 2000 Sep;23(3):223-39
references.pmid: 10942847
references.citation: EMBO J. 2001 May 1;20(9):2171-9
references.pmid: 11331583
references.citation: EMBO J. 2003 Jun 2;22(11):2679-91
references.pmid: 12773384
references.citation: Mol Biol Cell. 2003 Jul;14(7):2921-34
references.pmid: 12857875
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19132-7
references.pmid: 16365290
references.citation: Biol Psychiatry. 2006 May 1;59(9):793-800
references.pmid: 16325153
references.citation: J Biol Chem. 2006 Aug 18;281(33):23611-9
references.pmid: 16777849
references.citation: Hum Mol Genet. 2006 Oct 15;15(20):3024-33
references.pmid: 16959794
references.citation: J Neurosci. 2007 Jan 17;27(3):496-506
references.pmid: 17234582
references.citation: Mol Psychiatry. 2007 Nov;12(11):1026-32
references.pmid: 17387318
references.citation: Cell Physiol Biochem. 2007;20(6):687-702
references.pmid: 17982252
references.citation: Neurosignals. 2008;16(2-3):183-93
references.pmid: 18253057
references.citation: J Neurochem. 2008 May;105(4):1384-93
references.pmid: 18331582
references.citation: Genes Dev. 2008 May 1;22(9):1244-56
references.pmid: 18451111
references.citation: Nat Rev Mol Cell Biol. 2008 Jul;9(7):574-82
references.pmid: 18523436
references.citation: Am J Hum Genet. 2008 Oct;83(4):445-56
references.pmid: 18817904
references.citation: Int Rev Cell Mol Biol. 2008;270:145-79
references.pmid: 19081536
references.citation: Schizophr Res. 2009 Apr;109(1-3):80-5
references.pmid: 19237267
references.citation: Dev Cell. 2009 May;16(5):675-86
references.pmid: 19460344
references.citation: Cell Mol Life Sci. 2009 Aug;66(16):2677-89
references.pmid: 19434368
references.citation: Nat Rev Neurosci. 2009 Dec;10(12):850-60
references.pmid: 19927149
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2687-92
references.pmid: 20133810
references.citation: J Neurosci. 2010 Mar 24;30(12):4408-18
references.pmid: 20335477
references.citation: Nat Neurosci. 2011 Jan;14(1):54-61
references.pmid: 21102451