Regulation of GABAARs by Phosphorylation

Abstract

γ-Aminobutyric acid type A receptors (GABAARs) are the principal mediators of fast synaptic inhibition in the brain as well as the low persistent extrasynaptic inhibition, both of which are fundamental to proper brain function. Thus unsurprisingly, deficits in GABAARs are implicated in a number of neurological disorders and diseases. The complexity of GABAAR regulation is determined not only by the heterogeneity of these receptors but also by its posttranslational modifications, the foremost, and best characterized of which is phosphorylation. This review will explore the details of this dynamic process, our understanding of which has barely scratched the surface. GABAARs are regulated by a number of kinases and phosphatases, and its phosphorylation plays an important role in governing its trafficking, expression, and interaction partners. Here, we summarize the progress in understanding the role phosphorylation plays in the regulation of GABAARs. This includes how phosphorylation can affect the allosteric modulation of GABAARs, as well as signaling pathways that affect GABAAR phosphorylation. Finally, we discuss the dysregulation of GABAAR phosphorylation and its implication in disease processes.

Compromising the phosphodependent regulation of the GABA A R β3 subunit reproduces the core phenotypes of autism spectrum disorders

“…GABA A R expression in S408/9A mice. (A) Treatment of hippocampal slices from WT mice with 100 nM phorbol 12,13-dibutyrate (PDBU) increased pS408/9 immunoreactivity consistent with published studies demonstrating that both residues are substrates of PKC (8). In contrast, pS408/9 immunoreactivity was not detected in S408/9A mice.…”

“…Alterations in the efficacy of GABAergic inhibition mediated by β3-containing GABA A Rs are strongly linked to ASDs. Phosphorylation of GABA A Rs regulates their exocytosis and endocytosis, and thereby their residence time on the neuronal plasma membrane and accumulation at inhibitory synapses (8). Central to these regulatory processes is the phosphorylation of S408/9 in the β3 subunit, which reduces the affinity of GABA A Rs for the clathrin adaptor protein AP2, as measured by using synthetic peptides corresponding to the β3 subunit and purified AP2 (9,13).…”

“…S408/9 are substrates of cAMP-dependent PKA, PKC, Ca 2+ -calmodulin type 2-dependent protein kinases (Cam KIIs), and cGMPdependent protein kinase, and they are principally dephosphorylated by protein phosphatase 2A (8). S408/9 are the principal mediators of high-affinity binding to the clathrin adaptor molecule AP2 within the β3 subunit, and thereby facilitate GABA A R endocytosis (9).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Drug-Induced Neuroplasticity Postsynaptic inhibitory plasticity is also mediated by diverse mechanisms in different synapses. Similar to glutamatergic receptors, phosphorylation of postsynaptic GABA A receptors by protein kinases, including PKA, PKC, CaMKII, and Src, leads to changes in the integral anion channel function (reviewed in Nakamura et al, 2015). The effects of phosphorylation are dynamic (increases and decreases in receptor activity) and dependent on the subunit composition of the GABA A receptor in a fashion that is not fully known at present.…”

Regulating the Efficacy of Inhibition Through Trafficking of γ-Aminobutyric Acid Type A Receptors

“…For a more in-depth review of synaptic GABA A R trafficking and phosphorylation see Luscher et al (14) and Nakamura et al (15). In addition, we have attempted to emphasize the dynamics of GABA A R trafficking, the speed of which is often overlooked but has the potential to dramatically alter GABA A R number and subunit composition.…”