Abstract
GABA type A receptors (GABAARs) mediate the majority of fast inhibitory neurotransmission in the central nervous system (CNS). Most prevalent as heteropentamers composed of two α, two β, and a γ2 subunit, these ligand-gated ionotropic chloride channels are capable of extensive genetic diversity (α1-6, β1-3, γ1-3, δ, 𝜀, 𝜃, π, ρ1-3). Part of this selective GABAAR assembly arises from the critical role for γ2 in maintaining synaptic receptor localization and function. Accordingly, mutations in this subunit account for over half of the known epilepsy-associated genetic anomalies identified in GABAARs. Fundamental structure–function studies and cellular pathology investigations have revealed dynamic GABAAR trafficking and synaptic scaffolding as critical regulators of GABAergic inhibition. Here, we introduce in vitro and in vivo findings regarding the specific role of the γ2 subunit in receptor trafficking. We then examine γ2 subunit human genetic variation and assess disease related phenotypes and the potential role of altered GABAAR trafficking. Finally, we discuss new-age imaging techniques and their potential to provide novel insight into critical regulatory mechanisms of GABAAR function.
Highlights
The adult central nervous system (CNS) is critically dependent on fast inhibitory neurotransmission evoked by GABAA receptors (GABAARs)
In order to bridge the gap between known γ2 trafficking mechanisms, identified protein interaction sites and human pathology, we examined γ2 subunit genetic variation using the Genome Aggregation Database (Lek et al, 2016), a dataset of exome sequence data from 123,136 individuals and whole genome sequencing from 15,496 unrelated individuals without any severe pediatric disease and their first-degree relatives
Fluorescence resonance energy transfer (FRET) techniques have been limitedly applied to studying GABA type A receptors (GABAARs) trafficking or receptor subunit composition (Ding et al, 2010; Shrivastava et al, 2011), collectively suggesting imaging techniques will be a rich resource of novel GABAAR knowledge
Summary
The adult central nervous system (CNS) is critically dependent on fast inhibitory neurotransmission evoked by GABAA receptors (GABAARs). Frameshift mutations within the ICD (E402Dfs∗3 generating a stop codon at Y404X critical Src/Fyn phospho site discussed earlier; and S443delC resulting in an altered and elongated carboxy terminus with +50 novel AA) were associated with more moderate-severe phenotypes like GTCS and GEFS+ underscoring the importance for intracellular regulation via the ICD (Macdonald et al, 2012) Both deficits in GABAAR surface trafficking and the functional role of specific γ2 subunit regions are critical factors modulating phenotypic outcome, with some missense mutations resulting in phenotypes as severe as nonsense mutations. Other epileptic or developmental phenotypes include absence seizures, complex partial seizures, severe global developmental delay, tonic infantile spasms, autism disorder with learning difficulties, Rolandic epilepsy, or epilepsy with myoclonic-astatic seizures; ECD, extracellular amino-terminal domain; M1–M3, transmembrane regions 1–3; ICD, intracellular domain; ↓↓, reduced; ↑, increased; , observed; , unknown; -, not affected/changed; ↓, slightly reduced; ↔, possibly. Fluorescence resonance energy transfer (FRET) techniques have been limitedly applied to studying GABAAR trafficking or receptor subunit composition (Ding et al, 2010; Shrivastava et al, 2011), collectively suggesting imaging techniques will be a rich resource of novel GABAAR knowledge
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
