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

Vien, Thuy N. PhD*; Moss, Stephen J. PhD; Davies, Paul A. PhD

doi: 10.1213/ANE.0000000000001349
Neuroscience and Neuroanesthesiology

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 end points; 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, posttranslational 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 end points, both unintentionally through pathologic processes but potentially as a therapeutic target to adjust anesthetic-sensitive GABAARs.

Published ahead of print June 9, 2016.

From the *Department of Neuroscience, Tufts University School of Medicine, Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts; and Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts.

Published ahead of print June 9, 2016.

Accepted for publication February 16, 2016.

Funding: This work was supported by a grant from the Simons Foundation #206026 (to Dr. Moss); NIH-NINDS grants, NS051195, NS056359, NS081735, NS080064, and NS087662 (to Dr. Moss); and NIH-NIMH grant, MH097446, and Department of Defense (DOD), AR140209 (to Drs. Davies and Moss). Dr. Moss serves as a consultant for SAGE therapeutics and AstraZeneca, relationships that are regulated by Tufts University and do not pose a conflict of interest.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Paul A. Davies, PhD, Department of Neuroscience, Tufts University School of Medicine, South Cove 602, 136 Harrison Ave, Boston, MA 02111.

The information regarding synaptic γ-aminobutyric acid type A receptor (GABAAR) trafficking is limited compared with that known for glutamatergic receptors. Trafficking of extrasynaptic GABAARs is even less well described. This lack of understanding of the control and transport of this type of GABAAR is important, considering that extrasynaptic GABAARs appear to be a particularly key target for anesthetic agents.1–5 Increasing the trafficking of α4-containing GABAARs to extrasynaptic sites leads to an increase in tonic inhibitory current, enhancing the hypnotic and amnestic actions of etomidate and propofol.6 Exposure to etomidate and isoflurane has been recently described to have prolonged effects on cell surface expression of α5-containing GABAARs with a resulting increase in anesthetic sensitivity and memory impairment.7 Similarly, the proinflammatory cytokine, interleukin-1β, increases the trafficking of α5-containing GABAARs to the surface of hippocampal neurons, increasing the sensitivity to the immobilizing and memory impairment properties of general anesthetics.8,9 Surface levels of extrasynaptic GABAARs are altered in many disease states such as neurodevelopment disorders, alcoholism, and brain injury.10–12 A better understanding of the processes underlying the mechanism of GABAAR trafficking could pave the way for novel therapeutic targets that reverse the pathologic levels of receptor expression.13

This review will briefly summarize GABAAR structure and formation followed by descriptions of receptor trafficking and how phosphorylation can alter membrane expression of GABAAR subunits. For a more in-depth review of synaptic GABAAR trafficking and phosphorylation, see the studies reported by Luscher et al14 and Nakamura et al.15 In addition, we have attempted to emphasize the dynamics of GABAAR trafficking, the speed of which is often overlooked but has the potential to dramatically alter GABAAR number and subunit composition. Targeting receptor insertion and endocytosis could have fast and prolonged effects on GABAAR pharmacology.

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In the adult mammalian central nervous system (CNS), γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter. It is estimated that approximately one-quarter of all neurons use GABA as their primary neurotransmitter.16 GABA is synthesized in the brain from the decarboxylation of the excitatory neurotransmitter glutamate in a reaction catalyzed by l-glutamic acid decarboxylase (GAD).17 In the mammalian brain, GAD is encoded by 2 different genes to produce 2 isoforms with distinct expression patterns. GAD65 is restricted to nerve terminals where it is involved with the production of GABA for neurotransmission, whereas GAD67 expression is observed throughout the cell and is involved in the production of GABA for non-neurotransmission functions, such as synaptogenesis and neuroprotection.18 After synthesis, GABA is transported into synaptic vesicles by the vesicular inhibitory amino acid transporter, where it becomes available for release into the synaptic cleft. The actions of GABA are terminated by reuptake via the GABA transporters (GAT-1 to GAT-4), also known as sodium- and chloride-dependent GABA transporter 1 to 4.19 In humans, the majority of GABA reuptake is mediated by GAT-1 expressed at nerve terminals and astrocytic processes in neurons and glia, respectively.20,21

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GABAARs are ligand-gated chloride channels responsible for mediating fast inhibition in the CNS and are the prominent neurotransmitter receptor to which most general anesthetics bind and modulate. GABA binding generates a conformational change in the intrinsic chloride channel of the protein, allowing chloride ions to flow down its electrochemical gradient. During early development, high intracellular chloride concentrations result in a depolarizing response to GABA.22–24 In adult brains, the efflux of chloride by the K+/Cl cotransporter, KCC2, leads to lower intracellular chloride concentrations, resulting in GABA producing a hyperpolarizing response that reduces the probability that an action potential will be generated.

GABAARs belong to the cys-loop ion channel superfamily whose other members include the nicotinic acetylcholine receptors, glycine receptors, 5-hydroxytryptamine type III receptors (5-HT3) receptors, and zinc-activated channels.25 Cys-loop receptors are heteropentamers with an intrinsic ion channel assembled from various classes of subunits; 19 GABAAR subunits have been identified that belong to 8 different classes: α (1–6), β (1–3), γ (1–3), δ, ε, π, θ, and ρ (1–3).26,27 The GABA-binding site is located at the interface between α and β subunits with 2 agonist-binding sites per receptor, whereas the benzodiazepine-binding site lies at the interface between α and γ subunits.25

GABAAR subunits possess similar structures: a large extracellular N-terminal containing the characteristic cysteine-cysteine loop, 4 transmembrane domains (TM1–TM4), a large intracellular loop between TM3 and TM4 that is the most genetically divergent part of each subunit, and a short extracellular C-terminal.25,28 The intracellular loop dynamically regulates receptor activity by altering its trafficking and cell surface expression through protein-protein interactions with regulatory molecules, such as microtubule-binding proteins, kinase-anchoring protein, and cytoskeletal proteins, and acts as a site for posttranslational modifications including ubiquitination and phosphorylation.15,29

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GABAAR subunit composition influences GABAAR trafficking and therefore its cellular and subcellular localization. In addition, subunit composition establishes the physiologic and pharmacologic properties of the receptor.26,30 Despite the potential for a wide variety of possible subunit combinations in the assembly of GABAARs, in vivo expression of functional GABAAR subunit combinations is limited, being regulated both spatially and temporally.26 Within the CNS, GABAAR subtypes display distinct cellular and subcellular localization patterns.31–33 The most commonly encountered GABAAR is composed with a stoichiometry of 2α, 2β, and 1γ subunit.27,31,32,34 At sites further away from inhibitory synapses, or extrasynaptic sites, the δ subunit can replace γ to form GABAARs with pharmacologic properties that are distinct from γ-containing GABAARs.12,35,36

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To maintain the efficacy of inhibition, GABAAR subunits need to be packaged together to form pentameric receptors, trafficked to the cell surface, and then moved to the either synaptic or extrasynaptic locations. The low-ambient GABA in extracellular spaces is not sufficient to activate synaptic-type GABAARs, which are required to be localized at synaptic locations. Similarly, cells need to have extrasynaptic-type receptors in the correct place in order for them to generate tonic inhibition current.

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After translation, GABAARs are assembled within the endoplasmic reticulum (ER). Although the heteropentamer can be formed from many combinations of the 19 available subunits, in vivo studies have established that the number of combinations that can be properly assembled and trafficked to the membrane is reasonably limited.28,37 For example, although GABAARs composed of only α and β subunits are functional in expression studies and may occur in vivo where they are proposed to mediate tonic inhibition, αβγ-GABAAR and αβδ-GABAAR combinations are the most commonly observed GABAARs in vivo.38–42

In the ER, resident chaperone proteins such as calnexin and binding immunoglobin protein (BiP) facilitate the proper folding and assembly of the receptor; improperly assembled or misfolded receptors are directed toward degradation in proteasomes.43–46 The negative regulator of proteasomal degradation, Plic-1 (protein that links integrin-associated protein with the cytoskeleton-1) assists in stabilizing the receptor within the ER and facilitates its transport to the Golgi apparatus after assembly.47 Plic-1 interacts with the intracellular domains of GABAAR α and β subunits to regulate their transport through the secretory pathway.48 In the Golgi, GABAARs are further processed and sorted into secretory vesicles for insertion into the plasma membrane. The γ2-containing GABAARs are palmitoylated in the Golgi through serine residues within γ2 cytoplasmic domain by the Golgi-specific aspartate-histidine-histidine-cysteine (DHHC) zinc finger protein, a process critical for its accumulation at inhibitory synapses.49

Trafficking of GABAARs from the Golgi through secretory vesicles to the plasma membrane is promoted by interaction with cytoplasmic proteins such as brefeldin A–inhibited guanine nucleotide exchange factor 2, GABAAR-associated protein (GABARAP), phospholipase C (PLC)-related catalytically inactive proteins 1 and 2 (PRIP1/2), and N-ethylmaleimide–sensitive factor (NSF). Brefeldin A–inhibited guanine nucleotide exchange factor 2 assists in the translocation of proteins through the trans-Golgi network through interactions with the intracellular domains of GABAARβ subunits, although it has also been localized to endosomes and may influence endocytic recycling of GABAARs.50,51 GABARAP, a member of the membrane-associated proteins, interacts with microtubules and the intracellular domains of GABAAR γ subunits.52,53 Overexpression of GABARAP in expression systems and cultured neurons increases the membrane expression of γ2-containing GABAARs, suggesting that GABARAP may facilitate the translocation of GABAARs from intracellular compartments to the cell membrane.52,54,55 The evidence for this is further supported by the finding that PLC-related catalytically inactive proteins PRIP1 and PRIP2 competitively inhibit γ2 binding to GABARAP.56 As its name suggests, PRIPs are proteins related to PLC but lack their catalytic activity. PRIP1 and PRIP2 double-knockout mice exhibit reduced diazepam sensitivity and decreased surface benzodiazepine-binding sites, indicative of a reduction in the membrane surface expression of γ2-containing GABAARs.56–58 PRIP1 may also indirectly influence membrane trafficking of GABAARs by binding to and inhibiting protein phosphatase 1a.59 In addition, PRIP1 binds to the intracellular domains of the GABAAR β subunits.59 The hexameric adenosine triphosphate (ATP)ase, NSF, also directly binds the intracellular domains of GABAAR β subunits to increase receptor trafficking toward the membrane.60 In addition, NSF interacts with GABARAP within the Golgi apparatus, where it is proposed to facilitate the intracellular trafficking of GABAARs.61

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Through controlling the availability and numbers of GABAARs at the plasma membrane, GABAAR trafficking between intracellular compartments and the membrane is the determining factor in regulating GABAergic inhibition. At extrasynaptic sites, GABAARs are inserted into the plasma membrane after de novo assembly in the ER or reinserted after internalization.62,63 After insertion into extrasynaptic sites, the lateral diffusion of GABAARs in the lipid bilayer under Brownian diffusion is rapid; single-particle tracking experiments have measured the diffusion coefficient at extrasynaptic sites to be 0.2 μm2/s. This is in contrast to the diffusion coefficient at postsynaptic membrane, 0.03 μm2/s.64 The lateral diffusion of GABAARs to synaptic or extrasynaptic sites is influenced predominantly by subunit composition along with protein-protein interactions with scaffolding proteins such as gephyrin and cytoskeletal proteins such as radixin.28,45

Gephyrin, the key scaffolding protein at inhibitory synapses for glycine and GABAARs, is involved in the clustering of synaptic GABAAR subtypes at GABAergic synapses.65 Gephyrin directly binds to the intracellular domains of α1, α2, α3, α5, β2, β3, and γ2 subunits to anchor synaptic GABAAR subtypes to the cytoskeleton.27,34,66 Experiments with gephyrin knockout mice, along with antisense oligonucleotide knockdown of gephyrin, have demonstrated that inhibiting gephyrin expression significantly decreases γ2 punctate staining and GABAAR clustering at inhibitory synapses.67–70 Likewise, gephyrin clustering along with synaptic GABAAR clustering were abolished in γ2 knockout mice, suggesting an interdependence between gephyrin and synaptic GABAARs in the formation of inhibitory synapses.67 In addition to gephyrin, interactions with synaptic adhesion molecules such as collybistin, neurexin, and neuroligin promote the formation of inhibitory synapses. Collybistin, a membrane-associated guanine nucleotide exchange factor, directly binds gephyrin to facilitate its translocation to the plasma membrane surface.71,72 Presynaptically localized β-neurexin and postsynaptically localized neuroligin 2 promote inhibitory synaptogenesis by facilitating the proper alignment of the inhibitory synapse.27,37

Less is known about the mechanisms for anchoring extrasynaptic GABAARs to the cytoskeleton. The adaptor protein radixin, a member of the ezrin/radixin/moesin family, directly links the extrasynaptic α5 subunit to the actin cytoskeleton although its functional relevance has not been determined, because depleting radixin in neurons abolished α5 subunit clustering but had no effect on α5 surface expression or GABA-mediated tonic currents. However, radixin depletion, or reducing the α5 subunit clustering through a radixin point mutant that prevents activation via phosphorylation, did alter synaptic miniature inhibitory postsynaptic currents (mIPSCs). The mIPSCs were more frequent and slower decaying, suggesting that the α5 subunit was now contributing to synaptic GABAARs.73,74 The radixin-depleted mice also had memory impairments that occurred because of the prolonged synaptic inhibitory current.74 These studies demonstrate that pools of extrasynaptic α5 subunit–containing GABAARs can be trafficked to synaptic sites to directly change cellular and behavior properties.

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Internalization of GABAARs occurs at extrasynaptic sites by binding of the clathrin adaptor protein 2 (AP2) to the intracellular domain of the receptor. AP2 is a heterotetrameric protein composed of 4 subunits commonly called adaptins: α, β2, µ2, and σ2. The α and β2 adaptins bind to the plasma membrane and clathrin and are involved in the recruitment of accessory proteins to facilitate the assembly of clathrin-coated pits, µ2 adaptin is responsible for cargo recognition, and the σ2 adaptin stabilizes the adaptor complex.75–78

The µ2 adaptins responsible for cargo binding recognize at least 4 motifs within GABAARs: a dileucine motif in the GABAAR β2 subunit (L343L344), a 10-amino-acid atypical AP2-binding motif enriched with lysine and arginine residues within the intracellular domain in all β subunits, and in γ2 subunits: a 12-amino-acid domain analogous to the β subunit AP2-binding site and a tyrosine-based YGYECL motif.44,79–83 The AP2-binding sites within the β and γ2 subunits overlap with the major phosphorylation sites for protein kinase A (PKA) and protein kinase C (PKC) along with calcium/calmodulin-dependant kinase II and AKT for the β subunits and Fyn and Src-family of tyrosine kinase for the γ2 subunit: S409 for β1, S410 for β2, S408/9 for β3, and Y365/367 for γ2.84–93

After endocytosis, GABAARs can undergo ubiquitination and degradation within lysosomes or recycled for reinsertion back to the plasma membrane. Interactions with the cytoplasmic domains of β and γ subunits with lysosomal regulatory proteins such as Huntingtin-associated protein 1 and calcium-modulating cyclophilin ligand promote the recycling of receptors to the membrane surface.28,54,94,95

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In an unperturbed system, the steady-state responses observed during the course of an experiment give the impression of a stable receptor number at the cell surface. However, GABAAR insertion and endocytosis are constantly ongoing, allowing the neuron to finely tune the level of inhibition on a time scale that allows rapid adaptation. We describe here some key experimental estimates of the chronology of GABAAR trafficking (Figure 1).

Figure 1.

Figure 1.

Blocking endocytosis with the internally dialyzed peptide P4 (targets the function of the guanosine-5’-triphosphate (GTP)ase dynamin, which is responsible for endocytosis) resulted in an increase in hippocampal mIPSC amplitudes because of an increase in membrane GABAARs at the synapse. An increase was detected in <10 minutes after the establishment of the whole-cell configuration and reached a plateau at approximately 2-fold higher than that in control after 40 to 50 minutes.44,83

Using the peptide (pepβ3) that represents the minimal μ2-binding region in the GABAAR β3 subunit, the endocytosis of β3 subunit–containing GABAARs are reduced by competing with μ2. This peptide also increased mIPSC amplitudes; the increase being detected 10 minutes after pepβ3 was dialyzed into the neuron after the establishment of the whole-cell configuration. In hippocampal slices, an increase in mIPSC amplitude was noted in cornu ammonis area 1 (CA1) neurons with pepβ3 dialysis within minutes after attainment of the whole-cell configuration.96

In whole-cell recordings from cortical neurons, the mIPSC amplitude can be steady for >60 minutes. However, including in the pipette a peptide (YECL-pep) that competes with the binding of μ2 to γ2 subunits resulted in an increase in mIPSC that was detected after 10 minutes.80 When the peptide was chemically phosphorylated, it failed to affect mIPSC amplitude, demonstrating the role of phosphorylation.

In experiments with cortical neurons maintained in culture, biotinylation experiments using antibodies against GABAAR β3 subunit have demonstrated that, for a given population of surface GABAARs, constitutive endocytosis removes approximately 20% to 25% of total surface GABAARs within 30 minutes. Of these internalized GABAARs, approximately 30% are recycled back to the plasma membrane within 5 minutes, and approximately 70% are back within an hour.97 Internalized GABAARs can undergo lysosomal degradation, but this process is much slower with approximately 30% of the initially labeled GABAARs undergoing lysosomal degradation within 6 hours.

Bogdanov et al62 nucleofected complimentary DNA (cDNA) encoding β3 subunits containing the bungarotoxin (Bgt)-binding site peptide together with a green fluorescent pHluorin reporter into freshly isolated hippocampal neurons. After 12 to 14 days in vitro (DIV) neurons were exposed to red fluorescent rhodamine-conjugated Bgt (Rd-Bgt) then washed in unlabeled Bgt and the neurons florescence along with synaptic labeling was measured. They found that extrasynaptic GABAARs have a shorter residence time (a significant decrease within 10 minutes from the start of the experiment) on the cell surface compared with synaptic GABAARs.62 The same group examined insertion of GABAARs with Rd-Bgt in neurons whose constitutive endocytosis had been blocked and found newly inserted β3 subunit–containing GABAARs in the extracellular region within 5 minutes. This measurement for the insertion is consistent with other data from recombinant cells and neurons.47,98

There appears to be remarkable agreement in the timing of these finely orchestrated trafficking events. Biochemical, imaging, and electrophysiologic experiments are consistent in demonstrating a significant endocytosis occurring within 10 minutes, insertion 5 to 10 minutes, and the majority of surface GABAARs being recycled within an hour.

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Phosphorylation dynamically regulates the membrane expression of β- and γ2-containing GABAARs by inhibiting AP2 binding, leading to an increase in surface β- and γ2-GABAAR subtypes.44,99,100 When S408/9 of the GABAAR β3 subunit is not phosphorylated, the µ2 adaptin is able to bind with high affinity; phosphorylation of S408/9 significantly reduced µ2 binding to β3 subunit by 100-fold.29,44 As a result of this phosphorylation-mediated stabilization of β3-containing GABAARs, there was an increased GABAergic inhibition by increasing mIPSC amplitude and frequency.29 Therefore, phosphorylation of β3 within the AP2-binding motif reduced µ2 binding to the β3 subunit and increased its surface expression and GABAergic phasic inhibition. Similar to the PKC phosphorylation of the β3 subunit, µ2 binding to the γ2 subunit is similarly phospho-dependent. Tyrosine phosphorylation of Y365/367 within the intracellular domain of γ2 decreased AP2 binding and increased the surface expression of γ2-containing GABAAR subtypes and a subsequent increase in inhibitory post-synaptic current (IPSC) amplitude.80

Phosphorylation of T375 of the α1 subunit reduces the affinity to gephyrin, which leads to reduced synaptic clustering and a reduction in the amplitude of mIPSCs as these receptors are now free to diffuse away from the synaptic site.101

Trafficking of extrasynaptic GABAARs that mediate tonic inhibition is also sensitive to phosphorylation. PKC phosphorylation of the β2 subunit (at S410) reduced tonic GABAAR-mediated inhibition in thalamic and hippocampal neurons.102 Increasing neuronal activity activates L-type voltage-gated Ca2+ channels. The rise in Ca2+ current stimulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, which phosphorylates S283 of the GABAAR β3 subunit. The net result is a rapid (within 2 minutes of L-type voltage-gated Ca2+ channel activation) and prolonged increase in GABAARs on the surface membrane and an increased tonic inhibition.98 The restriction of α5 subunit–containing GABAARs to extrasynaptic sites through binding to radixin can be overcome by an activity-dependent dephosphorylation of radixin, which releases α5 subunit–containing GABAARs, resulting in their increased synaptic relocation.74

PKC-mediated phosphorylation regulates the cell surface expression of extrasynaptic α4-containing GABAARs through increasing the rate of insertion of α4 to the cell surface. In vitro experiments revealed that α4 subunits are phosphorylated in a PKC-dependent manner at serine 443 within the intracellular loop of α4, and phorbol ester activation of PKC increased α4 cell surface insertion.103 In addition, treatment with the neurosteroid tetrahydrodeoxycorticosterone (THDOC) increased the PKC-mediated membrane insertion of the extrasynaptic α4 subunit and enhanced tonic conduction. This phosphorylation change is independent of the ability of neurosteroids to allosterically potentiate the GABA-evoked current.13,103 When GABAARs are composed of α4 and β3 subunits, the combined effect of PKC phosphorylation is increased membrane insertion (α4 subunit effect) and membrane stability (β3 subunit effect), producing a rapid and prolonged increase in tonic current.

Furthermore, when S408/9 of β3 subunits have been mutated to alanines (S408/409A), the increase in α4 PKC-mediated phosphorylation is abolished and THDOC fails to increase the cell surface expression of the α4 subunit.104

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The amazing control and coordinated placement of GABAARs into synaptic and extrasynaptic sites allows for the specific types of GABAARs to be located where they mediate phasic and tonic inhibitory currents. Phosphorylation allows for changes in trafficking, in the rate of insertion or endocytosis, and the localization of particular subunits. Normal changes in neuronal activity and pathologic conditions such as seizures96 and inflammation8 can alter phosphorylation and impact the trafficking of GABAARs. Changes in trafficking could have a significant impact on anesthetic end points. For example, a PKC-mediated increase in extrasynaptic receptor insertion could increase the sensitivity of anesthetics to bring about loss of consciousness.6 Controlling receptor trafficking could provide a valuable therapeutic target to boost or reduce the level and efficacy of inhibition.

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Name: Thuy N. Vien, PhD.

Contribution: This author helped prepare the manuscript.

Name: Stephen J. Moss, PhD.

Contribution: This author helped prepare the manuscript.

Name: Paul A. Davies, PhD.

Contribution: This author helped prepare the manuscript.

This manuscript was handled by: Gregory J. Crosby, MD.

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