Regulation of GABAA Receptor Subunit Expression in Substance Use Disorders

Abstract

The modulation of neuronal cell firing is mediated by the release of the neurotransmitter GABA (γ-aminobuytric acid), which binds to two major families of receptors. The ionotropic GABAA receptors (GABA_ARs) are composed of five distinct subunits that vary in expression by brain region and cell type. The action of GABA on GABA_ARs is modulated by a variety of clinically and pharmacologically important drugs such as benzodiazepines and alcohol. Exposure to and abuse of these substances disrupts homeostasis and induces plasticity in GABAergic neurotransmission, often via the regulation of receptor expression. Here, we review the regulation of GABA_AR subunit expression in adaptive and pathological plasticity, with a focus on substance use. We examine the factors influencing the expression of GABA_AR subunit genes including the regulation of the 5' and 3' untranslated regions, variations in DNA methylation, immediate early genes and transcription factors that regulate subunit expression, translational and post-translational modifications, and other forms of receptor regulation beyond expression. Advancing our understanding of the factors regulating GABA_AR subunit expression during adaptive plasticity, as well as during substance use and withdrawal will provide insight into the role of GABAergic signaling in substance use disorders, and contribute to the development of novel targeted therapies.

Keywords: GABA; GABAA receptor; alcohol; benzodiazepines; expression; plasticity; substance use; substance use disorder; transcription; translation.

Figure 1

Levels of regulation impacting GABA_AR expression and function. Expression of a GABA_AR subunit begins with the initiation of transcription, which is controlled by a multiprotein complex that regulates the 5′UTR flanking genes encoding individual subunits. Transcription factors and other proteins that regulate transcription (yellow) bind to consensus sites in the 5′UTR and either promote or repress initiation. Many GABA_AR subunit 5′UTRs contain consensus sites for more than one transcription factor, as well as multiple transcription start sites (red). Additional phases of splicing and polyadenylation (green) occur in the nucleus prior to the shuttling of the transcript to the rough endoplasmic reticulum for translation at ribosomes (grey circles). Translation of the subunit transcripts has been shown to be regulated by RNA-binding proteins (RBPs; turquoise), as well as microRNAs (miRNAs; turquoise). Once translated, the subunits are assembled (blue) together in quaternary structure to form a functional heteropentameric GABA_AR. GABA_ARs are also subject to regulation via post-translational modifications (blue) such as phosphorylation and palmitoylation, as well as regulated targeting and trafficking to become preferentially localized to specific subcellular domains.

Figure 2

Overview of the major regulators of transcription and translation influencing the expression of GABA_AR subunits. Generally, the 5′ UTR of GABA_AR subunit genes contains multiple consensus sites for transcription factors (yellow), and in many cases, multiple transcription start sites (red). The majority of subunits lack canonical TATA and CCAAT sequences in their 5′UTRs. A number of regulators have been found to influence the transcription of multiple subunits including CREB and MeCP2. Maturation of the mRNA involves the addition of a 5′ cap as well as a poly-A tail adjacent to the 3′UTR. Mature GABA_AR transcripts are transported out of the nucleus to ribosomes on the rough endoplasmic reticulum, where translation is influenced by RNA-binding proteins (blue oval) such as FMRP, NONO, and Pum2, as well as by microRNAs (miRNAs; blue line).