Lorenz-Guertin Joshua M, Bambino Matthew J, Jacob Tija C
Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
Front Cell Neurosci. 2018 Aug 23;12:265. doi: 10.3389/fncel.2018.00265. eCollection 2018.
GABA type A receptors (GABARs) 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 GABAR 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 GABARs. Fundamental structure-function studies and cellular pathology investigations have revealed dynamic GABAR trafficking and synaptic scaffolding as critical regulators of GABAergic inhibition. Here, we introduce and 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 GABAR trafficking. Finally, we discuss new-age imaging techniques and their potential to provide novel insight into critical regulatory mechanisms of GABAR function.
GABA A型受体（GABARs）介导中枢神经系统（CNS）中大部分快速抑制性神经传递。这些配体门控离子型氯化物通道最常见的形式是由两个α、两个β和一个γ2亚基组成的异五聚体，具有广泛的遗传多样性（α1 - 6、β1 - 3、γ1 - 3、δ、ε、θ、π、ρ1 - 3）。这种选择性GABAR组装的部分原因是γ2在维持突触受体定位和功能方面起着关键作用。因此，该亚基的突变占GABARs中已知的与癫痫相关的遗传异常的一半以上。基础结构 - 功能研究和细胞病理学研究表明，动态GABAR转运和突触支架是GABA能抑制的关键调节因子。在这里，我们介绍关于γ2亚基在受体转运中具体作用的研究结果。然后，我们研究γ2亚基的人类遗传变异，并评估疾病相关表型以及GABAR转运改变的潜在作用。最后，我们讨论新时代成像技术及其为深入了解GABAR功能的关键调节机制提供新见解的潜力。
