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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 ?1, ?1, and ?2 ?-aminobutyric type A receptor (GABAAR) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the ?1, ?4, and ?1-3 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 ?1 subunit, more immature N-glycosylation of the 49-kDa ?1 subunit isoform, and altered total N-glycosylation of the ?2 GABAAR subunit in schizophrenia. Measures of altered N-glycosylation of the ?1 and ?2 subunits were confounded by an increased apparent molecular mass of all ?1 and ?2 subunit isoforms in schizophrenia. Although N-glycosylation of ?1, ?1, and ?2 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.

SUBMITTER: Mueller TM 

PROVIDER: S-EPMC3895232 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia.

Mueller Toni Marie TM   Haroutunian Vahram V   Meador-Woodruff James H JH  

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20130806 3


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,  ...[more]

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