title: Metabolomic Approaches to Defining the Role(s) of GABAρ Receptors in the Brain.
abstract: The inhibitory neurotransmitter γ-aminobutyric acid (GABA) acts through various types of receptors in the central nervous system. GABAρ receptors, defined by their characteristic pharmacology and presence of ρ subunits in the channel structure, are poorly understood and their role in the cortex is ill-defined. Here, we used a targeted pharmacological, NMR-based functional metabolomic approach in Guinea pig brain cortical tissue slices to identify a distinct role for these receptors. We compared metabolic fingerprints generated by a range of ligands active at GABAρ and included these in a principal components analysis with a library of other metabolic fingerprints obtained using ligands active at GABAA and GABAB, with inhibitors of GABA uptake and with compounds acting to inhibit enzymes active in the GABAergic system. This enabled us to generate a metabolic "footprint" of the GABAergic system which revealed classes of metabolic activity associated with GABAρ which are distinct from other GABA receptors. Antagonised GABAρ produce large metabolic effects at extrasynaptic sites suggesting they may be involved in tonic inhibition.
authors.affiliation: Neuroscience Research Australia, Barker St, Randwick, NSW, 2031, Australia, c.rae@unsw.edu.au.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rae
authors.forename: Fatima A
authors.initials: FA
authors.lastname: Nasrallah
authors.forename: Vladimir J
authors.initials: VJ
authors.lastname: Balcar
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Rowlands
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
authors.forename: Jane R
authors.initials: JR
authors.lastname: Hanrahan
mesh_terms: D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology*; D006168:Guinea Pigs; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods*; D010449:Peptide Mapping; D025341:Principal Component Analysis; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; D018079:Receptors, GABA; D018080:Receptors, GABA-B