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.

Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling

“…The first model contained data from a range of experiments using ligands active in the glutamatergic system (for list of ligands and experiments, see Appendix S1). The second model contained data from a range of experiments using ligands active in the GABAergic system (Nasrallah et al 2007(Nasrallah et al , 2010a(Nasrallah et al ,b, 2011Rae et al 2009Rae et al , 2014Rae et al , 2015.…”

Creatine as a booster for human brain function. How might it work?

“…GAA is an antagonist at GABAρ receptors [7] as are other guanidino compounds, which are also elevated in GAMT-deficiency [8]. These particular symptoms can be reduced by restricting arginine intake and thus reducing GAA levels.…”

“…The precursor, guanidinoacetate, is an agonist at GABA-A receptors and an antagonist at GABA-ρ, in the latter case at least at physiologically relevant concentrations [7]. Creatine may also be active at the receptor responding to the major excitatory neurotransmitter glutamate, the NMDA receptor (NMDAR).…”

Targeting GABAC Receptors Improves Post-Stroke Motor Recovery

“…By selecting compounds and dosing paradigms that selectively target individual GABA receptor subtypes, researchers have shown that the modulation of either tonic or phasic inhibition can enhance functional motor recovery in rodents after stroke [5,18,19]. GABAC receptors also known as GABAA rho () receptors are insensitive to bicuculline; they can be found extrasynaptically, and similar to other extrasynaptic GABAA receptors (e.g., α5-or δ-containing GABAA receptors), they do not readily desensitize in the presence of GABA [20,21]. In addition to modulating tonic inhibitory currents directly by targeting extrasynaptic GABAA receptors, we have recently also reported that targeting the astrocytic GABA transporter type 3 (GAT3) [22] using the substrate, L-isoserine, increases the expression of GAT3 and improves motor function [19].…”