Molecular Characterization of GABA-A Receptor Subunit Diversity within Major Peripheral Organs and Their Plasticity in Response to Early Life Psychosocial Stress

Abstract

Gamma aminobutyric acid (GABA) subtype A receptors (GABAARs) are integral membrane ion channels composed of five individual proteins or subunits. Up to 19 different GABAAR subunits (α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3) have been identified, resulting in anatomically, physiologically, and pharmacologically distinct multiple receptor subtypes, and therefore GABA-mediated inhibition, across the central nervous system (CNS). Additionally, GABAAR-modulating drugs are important tools in clinical medicine, although their use is limited by adverse effects. While significant advances have been made in terms of characterizing the GABAAR system within the brain, relatively less is known about the molecular phenotypes within the peripheral nervous system of major organ systems. This represents a potentially missed therapeutic opportunity in terms of utilizing or repurposing clinically available GABAAR drugs, as well as promising research compounds discarded due to their poor CNS penetrance, for the treatment of peripheral disorders. In addition, a broader understanding of the peripheral GABAAR subtype repertoires will contribute to the design of therapies which minimize peripheral side-effects when treating CNS disorders. We have recently provided a high resolution molecular and function characterization of the GABAARs within the enteric nervous system of the mouse colon. In this study, the aim was to determine the constituent GABAAR subunit expression profiles of the mouse bladder, heart, liver, kidney, lung, and stomach, using reverse transcription polymerase chain reaction and western blotting with brain as control. The data indicate that while some subunits are expressed widely across various organs (α3–5), others are restricted to individual organs (γ2, only stomach). Furthermore, we demonstrate complex organ-specific developmental expression plasticity of the transporters which determine the chloride gradient within cells, and therefore whether GABAAR activation has a depolarizing or hyperpolarizing effect. Finally, we demonstrate that prior exposure to early life psychosocial stress induces significant changes in peripheral GABAAR subunit expression and chloride transporters, in an organ- and subunit-specific manner. Collectively, the data demonstrate the molecular diversity of the peripheral GABAAR system and how this changes dynamically in response to life experience. This provides a molecular platform for functional analyses of the GABA–GABAAR system in health, and in diseases affecting various peripheral organs.

Therapeutically leveraging GABAA receptors in cancer

“…At least 19 genes code for different GABA A R subunits. 10,11 The complexity of possible GABA A Rs that may be formed from such a repertoire of genes is further expanded by alternative splicing, use of alternative promoters, and post-translational modification of subunits. At baseline, GABR genes contribute to the assembly of a ligand-gated pentameric chloride anion channel, the GABA A R. Most commonly, GABA A Rs are composed of two α, two β, and a γ-subunit encoded by GABR genes GABRA (1 to 6), GABRB (1 to 3), and GABRG (1 to 3), respectively.…”

GABAA Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome

“…There are two classes of GABA receptors, the heteropentameric anion-permeable GABA type A (GABA A ) receptor, which mediates fast inhibition (15), and the G-protein coupled GABA type B (GABA B ) receptor, which mediates slow inhibition (16). GABA A receptors consist of combinations of 19 different subunits (17). MRNA and protein of several of these receptor subunits are reduced in Fmr1 KO mouse brain (18)(19)(20)(21) and in humans (22).…”

Drug Repurposing Patent Applications January–March 2020

“…That GABAA receptors regulate stress and inflammation is well known, but the mechanisms are as complex as the receptor itself: pharmacologic activation of a3-GABAA receptors induces colon inflammation in mice, whereas ligands at a1/4/5-GABAARs are anti-inflammatory. 25,26 Outlines for possible clinical studies in inflammatory bowel syndrome and asthma are presented, but there are no data to support the claims. While there is limited evidence for GABAA receptors containing d-subunits being expressed in the gut, intestinal actions of gaboxadol might be explained by the gut-brain axis.…”