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Metabolomic Approaches to Defining the Role(s) of GABAρ Receptors in the Brain

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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.

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Acknowledgments

The authors are grateful to Dr Jim Hook, Dr Adele Amoore and Dr Don Thomas of the UNSW Mark Wainwright Analytical Centre for expert technical assistance.

Funding

This work was supported by UNSW, NewSouth Global and the National Health and Medical Research Council of Australia (#568767 & 630516).

Conflict of Interest

CDR has received a speaker honorarium from Philips Healthcare. BDR, GARJ, VJB, FAN and JRH have no conflict of interest to declare.

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Authors and Affiliations

  1. Neuroscience Research Australia, Barker St, Randwick, NSW, 2031, Australia

    Caroline Rae, Fatima A. Nasrallah & Benjamin D. Rowlands

  2. School of Medical Sciences UNSW, The University of New South Wales, Sydney, NSW, 2052, Australia

    Caroline Rae & Benjamin D. Rowlands

  3. Bosch Institute and School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia

    Vladimir J. Balcar

  4. Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia

    Graham A. R. Johnston

  5. Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia

    Jane R. Hanrahan

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  1. Caroline Rae
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  2. Fatima A. Nasrallah
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  3. Vladimir J. Balcar
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  4. Benjamin D. Rowlands
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  5. Graham A. R. Johnston
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  6. Jane R. Hanrahan
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Correspondence to Caroline Rae.

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Rae, C., Nasrallah, F.A., Balcar, V.J. et al. Metabolomic Approaches to Defining the Role(s) of GABAρ Receptors in the Brain. J Neuroimmune Pharmacol 10, 445–456 (2015). https://doi.org/10.1007/s11481-014-9579-4

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  • DOI: https://doi.org/10.1007/s11481-014-9579-4

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