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

Abstract

Trafficking of anesthetic-sensitive receptors within the plasma membrane, or from one cellular component to another, occurs continuously. Changes in receptor trafficking have implications in altering anesthetic sensitivity. γ-aminobutyric acid type A receptors (GABAARs) are anion permeable ion channels and are the major class of receptor in the adult mammalian central nervous system that mediates inhibition. GABAergic signaling allows for precise synchronized firing of action potentials within brain circuits that is critical for cognition, behavior, and consciousness. This precision depends upon tightly controlled trafficking of GABAARs into the membrane. General anesthetics bind to and allosterically enhance GABAARs by prolonging the open state of the receptor and thereby altering neuronal and brain circuit activity. Subunit composition and GABAAR localization strongly influence anesthetic endpoints, therefore, changes in GABAAR trafficking could have significant consequences to anesthetic sensitivity. GABAARs are not static membrane structures but are in a constant state of flux between extrasynaptic and synaptic locations and are continually endocytosed and recycled from and to the membrane. Neuronal activity, post-translational modifications, and some naturally occurring and synthetic compounds can influence the expression, and trafficking of GABAARs. In this article we review GABAARs, their trafficking and how phosphorylation of GABAAR subunits can influence the surface expression and function of the receptor. Ultimately, alterations of GABAAR trafficking could modify anesthetic endpoints, both unintentionally through pathological processes but potentially as a therapeutic target to adjust anesthetic-sensitive GABAARs.

Metabotropic, but not allosteric, effects of neurosteroids on GABAergic inhibition depend on the phosphorylation of GABAA receptors

“…NAS are accepted to play key roles as endogenous modulators of GABAergic inhibition, in part by acting as GABA A R PAMs (1,8). Recent studies have suggested that, in addition to their role as PAMs, NASs exert sustained metabotropic effects on GABAergic inhibition via an underlying mechanism that remains ill-defined (10,30). In addition to its role as a GABA A R PAM, ALLO has been shown to bind and activate mPRs, which have been proposed to be a novel family of GPCRs that are highly expressed in the brain (12)(13)(14)(15)(16)(17).…”

SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAA Receptor γ2 Subunit

“…The γ2 subunit is important for efficient trafficking of GABA A Rs to the cell membrane (Nakamura et al, 2015 ; Vien et al, 2016 ) and for GABA A R clustering at synapses (Essrich et al, 1998 ; Alldred et al, 2005 ). Hereditary epilepsy mutations to γ2 impair channel function by various means including ER retention of misfolded subunits, mutant subunit aggregation, dominant negative suppression of partner subunits, impaired channel gating and aberrant synaptic targeting (Kang and Macdonald, 2016 ).…”

News about non-secretory exocytosis: mechanisms, properties, and functions

“…The main task of these vesicles is the transport of specific membrane proteins, synthesized in the endoplasmic reticulum (ER), to critical sites of the cell surface. Transported proteins include subunits and/or whole proteins of receptors, channels, pumps, transporters, and others (Flowerdew and Burgoyne, 2009; Dumoulin et al, 2011; Luscher et al, 2011; Tanaka and Hirano, 2012; Jurado et al, 2013; Martinez-Mamol et al, 2013; Hussain and Davanger, 2015; Gu et al, 2016; Gu and Huganir, 2016; Hussain et al, 2016; Langlhofer and Villmann, 2016; Meneses et al, 2016; Vien et al, 2016; Jaldin-Fincati et al, 2017; Klemens et al, 2017; Pick et al, 2017; Roth et al, 2017; Wu et al, 2017).…”

“…Also in this case, the SNARE complexes that govern the exocytosis of resting and stimulated vesicles are different (Gu and Huganir, 2016; Hussain et al, 2016). The vesicles of subunits of other receptors, the inhibitory GABA A and glycine receptors, are also involved in non-secretory exocytosis, analogous to those of glutamate receptors (Dumoulin et al, 2011; Luscher et al, 2011; Langlhofer and Villmann, 2016; Vien et al, 2016). In neurons, therefore, the specific roles of the receptors and their subunits strongly suggest that the exocytosis of many non-secretory vesicles, distinct in terms of specificity, participates in distinct physiological functions.…”

“…Numerous non-secretory vesicles of the first group, transporting to the plasma membrane subunits of ionic receptors necessary for their postsynaptic function, have already been described (Dumoulin et al, 2011; Luscher et al, 2011; Tanaka and Hirano, 2012; Jurado et al, 2013; Hussain and Davanger, 2015; Gu et al, 2016; Gu and Huganir, 2016; Hussain et al, 2016; Langlhofer and Villmann, 2016; Vien et al, 2016; Chiu et al, 2017; Fujii et al, 2017; Lesteberg et al, 2017; Roth et al, 2017; Wu et al, 2017). The events occurring on axons are more complex (Figure 3A–C).…”