title: Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.
abstract: Inhibitory neurotransmission is primarily mediated by γ-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABA(A)R). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the α1-6, β1-3 or γ2 GABA(A)R subunits in the superior temporal gyrus (STG) in schizophrenia, the α1, β1 and β2 GABA(A)R subunits are abnormally N-glycosylated. N-glycosylation is a posttranslational modification that has important functional roles in protein folding, multimer assembly and forward trafficking. To investigate the impact that altered N-glycosylation has on the assembly and trafficking of GABA(A)Rs in schizophrenia, this study used western blot analysis to measure the expression of α1, α2, β1, β2 and γ2 GABA(A)R subunits in subcellular fractions enriched for endoplasmic reticulum (ER) and synapses (SYN) from STG of schizophrenia (N = 16) and comparison (N = 14) subjects and found evidence of abnormal localization of the β1 and β2 GABA(A)R subunits and subunit isoforms in schizophrenia. The β2 subunit is expressed as three isoforms at 52 kDa (β2(52 kDa)), 50 kDa (β2(50 kDa)) and 48 kDa (β2(48 kDa)). In the ER, we found increased total β2 GABA(A)R subunit (β2(ALL)) expression driven by increased β2(50 kDa), a decreased ratio of β(248 kDa):β2(ALL) and an increased ratio of β2(50 kDa):β2(48 kDa). Decreased ratios of β1:β2(ALL) and β1:β2(50 kDa) in both the ER and SYN fractions and an increased ratio of β2(52 kDa):β(248 kDa) at the synapse were also identified in schizophrenia. Taken together, these findings provide evidence that alterations of N-glycosylation may contribute to GABAergic signaling deficits in schizophrenia by disrupting the assembly and trafficking of GABA(A)Rs.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Mueller
authors.affiliation: 1] Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA [2] Science and Technology Honors Program, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Remedies
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Meador-Woodruff
mesh_terms: D000368:Aged; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D004721:Endoplasmic Reticulum / Q000737:chemistry; D005260:Female; D006031:Glycosylation; D006801:Humans; D008297:Male; D011963:Receptors, GABA-A / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D018080:Receptors, GABA-B / Q000378:metabolism / Q000502:physiology; D012559:Schizophrenia / Q000378:metabolism* / Q000503:physiopathology; D013347:Subcellular Fractions / Q000737:chemistry; D013569:Synapses / Q000737:chemistry; D013702:Temporal Lobe / Q000737:chemistry
chemical_list: C485503:GABBR2 protein, human; C546240:GABRA1 protein, human; C546264:GABRB1 protein, human; C495710:GABRB2 protein, human; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B