title: N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia.
abstract: The molecular mechanisms of schizophrenia have been under investigation for decades; however, the exact causes of this debilitating neuropsychiatric disorder are still unknown. Previous studies have identified multiple affected neurotransmitter systems, brain regions, and cell types, each making a unique contribution to symptom presentation and pathophysiology. Numerous studies have identified gene and protein expression changes in schizophrenia, but the role of post-translational modifications, specifically N-glycosylation, has only recently become a target of investigation. N-glycosylation of molecules associated with glutamatergic neurotransmission is disrupted in schizophrenia, but it was unknown if these alterations are exclusive to the glutamatergic system or due to a more generalized deficit.In normal human cortex, we found evidence for N-glycosylation of the α1, β1, and β2 γ-aminobutyric type A receptor (GABAAR) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the α1, α4, and β1-3 GABAAR subunits. Examining GABAAR subunit N-glycosylation in matched pairs of schizophrenia (N=14) and comparison (N=14) of superior temporal gyrus revealed a smaller molecular mass of immature N-glycans on the α1 subunit, more immature N-glycosylation of the 49-kDa β1 subunit isoform, and altered total N-glycosylation of the β2 GABAAR subunit in schizophrenia. Measures of altered N-glycosylation of the β1 and β2 subunits were confounded by an increased apparent molecular mass of all β1 and β2 subunit isoforms in schizophrenia. Although N-glycosylation of α1, β1, and β2 were all changed in schizophrenia, the concentrations of GABAAR subunits themselves were unchanged. These findings suggest that disruptions of N-glycosylation in schizophrenia are not exclusive to glutamate and may indicate a potential disruption of a central cell signaling process in this disorder.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Toni Marie
authors.initials: TM
authors.lastname: Mueller
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Meador-Woodruff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D005260:Female; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011180:Postmortem Changes; D021122:Protein Subunits / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000473:pathology*; D013702:Temporal Lobe / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D011963:Receptors, GABA-A
references.citation: Mol Pharmacol. 1994 Nov;46(5):858-65
references.pmid: 7969072
references.citation: Curr Top Med Chem. 2002 Aug;2(8):795-816
references.pmid: 12171572
references.citation: FEBS Lett. 1991 Aug 5;287(1-2):27-30
references.pmid: 1715287
references.citation: Neurochem Int. 1999 May;34(5):379-85
references.pmid: 10397365
references.citation: J Proteome Res. 2012 Jul 6;11(7):3743-52
references.pmid: 22594947
references.citation: J Psychiatr Res. 2009 Jul;43(11):970-7
references.pmid: 19321177
references.citation: Neuron. 2006 Oct 5;52(1):155-68
references.pmid: 17015233
references.citation: Arch Neurol. 2006 Oct;63(10):1372-6
references.pmid: 17030651
references.citation: Am J Psychiatry. 1990 Nov;147(11):1457-62
references.pmid: 2221156
references.citation: Schizophr Res. 2013 May;146(1-3):177-83
references.pmid: 23462048
references.citation: J Biol Chem. 2010 Oct 8;285(41):31348-61
references.pmid: 20639197
references.citation: Am J Hum Genet. 2008 Jun;82(6):1249-61
references.pmid: 18514161
references.citation: Biol Psychiatry. 1993 Feb 15;33(4):255-60
references.pmid: 8471678
references.citation: Neuropharmacology. 2012 Mar;62(3):1574-83
references.pmid: 21277876
references.citation: Traffic. 2009 Nov;10(11):1569-78
references.pmid: 19761541
references.citation: Cortex. 2013 Apr;49(4):1063-72
references.pmid: 23040316
references.citation: Neurosci Lett. 1991 Aug 19;129(2):237-41
references.pmid: 1660579
references.citation: Schizophr Bull. 1998;24(3):325-41
references.pmid: 9718627
references.citation: Schizophr Res. 2010 Mar;117(1):92-8
references.pmid: 19716271
references.citation: Brain Res. 2006 Dec 6;1123(1):1-11
references.pmid: 17045977
references.citation: Proteomics. 2004 Jun;4(6):1537-50
references.pmid: 15174124
references.citation: J Neural Transm (Vienna). 2009 Apr;116(4):487-91
references.pmid: 19139805
references.citation: Cell. 2006 Sep 8;126(5):855-67
references.pmid: 16959566
references.citation: Neuropsychopharmacology. 2013 Sep;38(10):1910-20
references.pmid: 23571678
references.citation: Brain Res Rev. 2009 Jun;61(1):14-32
references.pmid: 19348859
references.citation: J Biol Chem. 1996 Jan 5;271(1):89-96
references.pmid: 8550630
references.citation: Br J Psychiatry. 2010 May;196(5):412-3
references.pmid: 20435970
references.citation: Brain Res. 2011 Sep 21;1413:98-114
references.pmid: 21840506
references.citation: Sci Rep. 2011 Sep 13;1:
references.pmid: 22034591
references.citation: Curr Psychiatry Rep. 2010 Aug;12(4):335-44
references.pmid: 20556669
references.citation: Schizophr Res. 2005 Sep 15;77(2-3):241-52
references.pmid: 15923110
references.citation: Nature. 1995 Nov 9;378(6553):176-9
references.pmid: 7477318
references.citation: Annu Rev Biochem. 2004;73:1019-49
references.pmid: 15189166
references.citation: Neuroreport. 2013 Aug 21;24(12):688-91
references.pmid: 23820740
references.citation: J Biol Chem. 2012 Apr 6;287(15):12083-97
references.pmid: 22303015
references.citation: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references.pmid: 15803162
references.citation: Mol Cell Proteomics. 2012 Jan;11(1):M111.011445
references.pmid: 22338125
references.citation: Schizophr Res. 2000 Jan 21;41(2):303-12
references.pmid: 10708339
references.citation: Exp Brain Res. 2006 Jan;168(4):587-90
references.pmid: 16362364
references.citation: Biochem J. 2000 May 15;348 Pt 1:1-13
references.pmid: 10794707
references.citation: Arch Gen Psychiatry. 1998 Mar;55(3):205-11
references.pmid: 9510214