Understanding the GABA A Receptor: Implications for Anesthesia and Beyond

Abstract Gamma-aminobutyric acid (GABA), a nonpeptide amino acid transmitter, is a major component of modern neuropharmacology and one of the most crucial target sites for general anesthetics and therapeutic drugs. GABA type A receptors (GABA A Rs) are the most abundant inhibitory neurotransmitter receptors in the central nervous system. They are part of the rapid-acting, ligand-gated ion channel (LGIC) receptor category, a pentameric Cys-loop superfamily member that mediates inhibitory neurotransmission in the mature brain. GABA A Rs mainly consist of two α subunits, two β subunits, and one additional subunit from either γ or δ arranged around a central chloride (Cl - ) selective channel. Multiple GABA A R subunit subtypes and splice variants have been identified. Each variant of GABA A R exhibits distinct biophysical and pharmacologic properties. Several compounds allosterically modulate the GABA A R positively or negatively. The widely used positive GABA A R modulators include benzodiazepines (anxiolytic and anticonvulsant), general anesthetics (volatile agents like isoflurane, and intravenous agents like barbiturates, etomidate, and propofol), long-chain alcohols, some anticonvulsants, and neuroactive steroids. The binding sites for each drug are distinctly different. The anesthetic drugs enhance receptor-mediated synaptic transmission and thus interrupt the thalamocortical transmission, which controls the sleep–wake patterns. Abnormality in the GABA A R function has been implicated in several neurological conditions, such as sleep disorders, seizures, depression, cognitive function, neurological recovery after injury, and neuroplasticity. Understanding the GABA A R lays the foundation for the development of highly specific drugs in the treatment of neurological disorders and general anesthesia.


Introduction
Gamma-aminobutyric acid (GABA), a nonpeptide amino acid, is the primary inhibitory neurotransmitter in the brain and a major inhibitory transmitter in the spinal cord, acting through the GABA receptor.The various levels of amnesia and loss of consciousness produced by many current general anesthetics such as benzodiazepines, barbiturates, propofol, etomidate, and volatile anesthetics are also mediated via their effects at the GABA receptor, notably the type A GABA receptor (GABA A R).The advances in modern molecular pharmacology and neuroscience have enabled investigators to understand the role of GABA A R in physiological and pathological conditions.Modulation of GABA A R is also one of the major components of modern neuropharmacology for several disorders.Understanding GABA A R has received a great deal of attention in the search for highly specific drug targets in the central nervous system (CNS).This narrative review gives a brief overview of the biochemistry Keywords ► GABA ► GABA A receptor ► isoforms ► general anesthesia ► modulation ► neurological disorders

Abstract
Gamma-aminobutyric acid (GABA), a nonpeptide amino acid transmitter, is a major component of modern neuropharmacology and one of the most crucial target sites for general anesthetics and therapeutic drugs.GABA type A receptors (GABA A Rs) are the most abundant inhibitory neurotransmitter receptors in the central nervous system.They are part of the rapid-acting, ligand-gated ion channel (LGIC) receptor category, a pentameric Cys-loop superfamily member that mediates inhibitory neurotransmission in the mature brain.GABA A Rs mainly consist of two α subunits, two β subunits, and one additional subunit from either γ or d arranged around a central chloride (Cl -) selective channel.Multiple GABA A R subunit subtypes and splice variants have been identified.Each variant of GABA A R exhibits distinct biophysical and pharmacologic properties.Several compounds allosterically modulate the GABA A R positively or negatively.The widely used positive GABA A R modulators include benzodiazepines (anxiolytic and anticonvulsant), general anesthetics (volatile agents like isoflurane, and intravenous agents like barbiturates, etomidate, and propofol), long-chain alcohols, some anticonvulsants, and neuroactive steroids.The binding sites for each drug are distinctly different.The anesthetic drugs enhance receptor-mediated synaptic transmission and thus interrupt the thalamocortical transmission, which controls the sleep-wake patterns.Abnormality in the GABA A R function has been implicated in several neurological conditions, such as sleep disorders, seizures, depression, cognitive function, neurological recovery after injury, and neuroplasticity.Understanding the GABA A R lays the foundation for the development of highly specific drugs in the treatment of neurological disorders and general anesthesia.
of GABA A R, including structure, function, and modulation by drugs and disease.

The GABAergic System
The GABAergic system of the brain consists of GABA-releasing cells and receptors that bind GABA.The GABA-releasing cells are incredibly diverse.They control the activity of local networks (interneurons) and form the output of some areas of the brain and nuclei (e.g., striatal medium spiny neurons and cerebellar Purkinje cells).GABA neurons are involved in the transmission of afferent pain signals and descending pain-modulating pathways.The GABA receptors are virtually located on every neuron in the brain and represent a diverse array of receptor types.GABA signaling also plays a vital role in controlling neuronal differentiation during development. 1n the spinal cord, GABA neurons have ubiquitous distribution with maximal concentration in the dorsal gray matter, followed by the ventral gray and white matter. 2

GABA Receptors
Three types of GABA receptors are described: type A (GABA A R), type B (GABA B R), and type C (GABA C R). GABA A Rs are fast-acting, ligand-gated, chloride ion channel (LGIC) receptors that mediate inhibition in the brain. 3,4GABA B Rs are relatively slow, class C of G-protein-coupled receptors. 5ABA C R, also named GABA-A-rho, is now classified as a subtype of GABA A R. GABA is more selective and nearly 10 times more potent at GABA C than GABA A receptors due to the higher number of agonist-binding sites in the GABA C complex.The structural and pharmacological action of these three receptors is illustrated in ►Table 1. GABA A R is the most abundant fast inhibitory neurotransmitter receptor in the CNS.It is a member of the pentameric Cys-loop superfamily.The other receptors of this family are the nicotinic acetylcholine, glycine, 5-HT3, and zinc-activated receptors.The intercellular communication mediated by GABA receptor activation differs from the "point-to-point" communication that underlies the synaptic transmission or the gap junction-mediated electrical coupling.It is more akin to the paracrine transmission associated with the actions of neuromodulators such as serotonin, histamine, dopamine, acetylcholine, and peptides in the brain.6

Structure and DIstribution of GABAA Receptor
GABA A R mainly consists of two α subunits, two β subunits, and one additional subunit from either a γ or d, arranged as a pentameric ring around a central chloride selective channel (►Fig.1A).When the receptor is activated, this ring serves as a channel through which chloride ions pass (►Fig.1B).The receptor has extracellular, transmembrane, and cytosolic domains.Each subunit comprises of a long N-terminal extracellular hydrophilic domain, four transmembrane-α-helices (TM1-TM4), three inter-helix loops, and a short C-terminal extracellular domain [7][8][9] (►Fig.1C).
The GABA A pentamer receptor includes various isoforms, and the possible arrangement of these isoforms is illustrated in ►Fig.2A.The common GABA A R isoforms in the brain are αβγ and αβd receptors.About 19 GABA A R subunit subtypes and splice variants have been identified: α (1-6), β (1 to 3), γ (1 to 3), d, ε, π, u and ρ (1-3) 7 (►Fig.2B).Each of the receptor subtypes exhibits distinct pharmacological and electrophysiological properties.These physiological and pharmacological properties of a receptor are determined by subunit composition, their arrangement, and developmental expression pattern. 10The properties of the subunits of α are mentioned in ►Table 2. Recently, Laverty et al developed a high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L isoform of the synaptic GABA A R. 11 The cryo-EM structure demonstrates the organization of heterooligomeric GABA A R receptors and provides a reference framework for the future of molecular principles of GABAergic signaling and pharmacology.The stoichiometry and subunit arrangement of αβγ receptors are well established, but the αβd receptors need further research.
The distribution and function of the receptor subtypes are varied.The α1β2γ2 GABA A R subtype is distributed in the thalamus.The α5βγ2 GABA A R subunits are distributed in the hippocampus and neocortical pyramidal cells.The d subunits coassemble with α6 subunits in the cerebellum and with α4 subunits in the hippocampus, striatum, thalamus, and cortex.The vital role of maintaining an inhibitory tone is contributed by the β3 subunit.Both GABA A R GABA B Rs have been located in the spinal cord.GABA A Rs are uniformly distributed in the gray matter (on dorsal and ventral interneurons), while GABA B Rs are spread in the dorsal horn (laminae I-III), both having a presynaptic location on primary afferent fibers and mediate synaptic inhibition. 2,12,13These GABA neurons enable excitatory proprioceptive signal integration, which permits the spinal cord to amalgamate sensory information and create smooth movements. 14,15Direct GABA A R or GABA B R-mediated inhibition of opioid-containing neurons facilitates pain transmission by reducing the release of these endogenous analgesics.GABAergic neurons located in the gray matter, anterior horn, and the substantia gelatinosa of Rolando explain the muscle relaxant effect of benzodiazepines.

GABAergic Inhibition
The GABA A Rs are most prevalent, localized mainly in the synapses. 16However, GABA A Rs do not exclusively locate to synapses.A small portion of the receptor subtypes, like α5βγ GABA A R and others containing the d subunit like the αβd receptors, has been found in the extrasynaptic regions (►Fig.3).
Three kinetically distinct forms of GABA A R-mediated inhibition are exhibited: (i) Rapid phasic inhibition at synaptic GABA A Rs-The α 1β2γ2 GABA A R mediates phasic inhibition in response to transient high concentrations of synaptic GABA release 17 (►Fig.4A) (ii) Persistent tonic inhibition at extrasynaptic receptors-Mediated by α 4β2d GABA A Rs.When activated by lowconcentration extrasynaptic GABA, they produce tonic inhibitory currents 17 (►Fig.4B).(iii) A prolonged albeit phasic "spillover" inhibitory postsynaptic current.GABA spilling from the synaptic cleft can activate presynaptic terminals receptors or neighboring synapses on the same or adjacent neurons to produce inhibitory postsynaptic currents (IPSCs) (►Fig.4C).
Any disturbance in the phasic or tonic inhibition is associated with many neurological and psychiatric diseases.Thus, modulating these signals has led to the basis of drug therapy as well as anesthesia.

Role of Extrasynaptic GABA A Receptors
Tonic inhibition produced by extrasynaptic inhibition is vital in regulating states of consciousness.The extrasynaptic GABA A Rs are essential targets for anesthetics, sleep-promot-ing drugs, neurosteroids, and alcohol.Disorders such as schizophrenia, epilepsy, and Parkinson's disease are found to involve disruptions in network dynamics associated with alterations in the tonic GABA A R-mediated conductance.The extrasynaptic GABA A Rs are potential therapeutic targets for the treatment of these diseases to enhance cognition and aid post-stroke functional recovery.
of an agonist to GABA A R causes activation of the LGIC (which facilitates the selective flow of permeant ions across the plasma membrane) and affects cell excitability.But sustained binding of the agonist renders LGICs to enter a shut state, which is refractory to activation, called the desensitized state. 19The exact roles of desensitization in vivo are still controversial.Still, they may include the prolongation of synaptic currents, decrement of responses during high-frequency neurotransmitter release, and modulation of extrasynaptic receptors subjected to tonic activation by low ambient concentrations of neurotransmitters. 20-23

Pharmacological Modulation of GABA A Receptors
Several compounds allosterically modulate the GABA A R positively or negatively in the presence of GABA.The widely used positive GABA A R modulators include benzodiazepines (anxiolytic and anticonvulsant), general anesthetics (volatile agents like isoflurane, and intravenous agents like barbitu-rates, etomidate, and propofol), long-chain alcohols, some anticonvulsants, and some neuroactive steroids. 7The notable negative GABA A R modulator includes proconvulsant flumazenil.

Mechanism of Modulation
GABA binding to the GABA A R increases the opening of the chloride ion channel.Many potent general anesthetics allosterically enhance the activation of GABA A Rs by decreasing the kind of the receptor. 24,25This enhanced GABA A R function comes about by at least four actions: enhanced affinity at the GABA binding site, enhanced channel opening, conductance, and modulation.At high concentrations, they cause direct activation of GABA A R. General anesthetics also inhibit GABA uptake into neurons and glia, thus increasing GABA concentrations at postsynaptic GABA A Rs. 26 (►Fig.5)

Differences in the GABA A R Enhancement by General Anesthetics
Although all anesthetics have principal effects on the GABA A R, the binding sites are distinctly different.The details of the binding sites of various drugs on the subunits  of GABA A R are mentioned in ►Table 3 and ►Fig.6A.There is good evidence that the intravenous anesthetics act near the extracellular end of the membrane-spanning domain (M) of various subunits.Amino acid residues located in the nonchannel lining face of the M1, M3, and M4 α-helices have been proposed as the binding sites for a range of compounds, including neurosteroids and general anesthetics. 27The differences in their effects are explained by the differences in affinity for the high agonist efficacy of GABA αβγ receptors and intermediate action at the αβd receptors. 28he general anesthetics act by selectively binding to the transmembrane intersubunit pockets of αβγ receptors.The α 1β2γ2 GABA A R has five subunit interfaces that harbor sites for drug binding and functional modulation of GABA A R, and each compound uses a different set of subunit interfaces: (i) Etomidate acts predominantly at interface 1 and γ þ/β subunit interfaces, propofol acts predominantly at interface 1, interface 2, γ þ/β, and pentobarbital acts predominantly at interface 2 and additionally at α þ/β-, and/or α þ/γ subunit interfaces.The asymmetry in anesthetic potentiation of the α 1β2γ2 GABA A R contributes to the differences in their effects 29 (►Fig.6B).

Influence of Isoform on Anesthetic Drug Effects
The subunit composition of the GABA A R plays a key role in determining the sensitivity to agonists, antagonists and modulators.1][32][33][34][35] The influence of the isoforms on anesthetic drug effects is shown in ►Table 4.

Functional Effects of Anesthetics on GABA A R in the Thalamocortical Pathway
The thalamus has a pivotal role in controlling conscious state transitions and has been recognized as an essential locus for anesthetic-induced sedation and hypnosis.There is impairment of thalamocortical (GABAergic neurons projecting from the thalamic reticular nucleus (TRN) toward the ventral basalis [VB]) and corticocortical projections during the general-anesthetic-induced unconscious state.Glutamatergic cells from the ventro-postero-medial nucleus (VPM) and cortex loop with the GABAergic TRN neurons.The excitatory glutamatergic pathway offers a tonic depolarization of the VPM neurons in the wakeful, activated state.It prevents them from entering synchronized, oscillatory states, which close the "gate" of the information procession. 36The anesthetic drugs enhance the GABA A R-mediated synaptic transmission and inhibit these glutamatergic pathways, thus interrupting the thalamocortical transmission.The extent of this inhibition determines the level of consciousness.The neural reactivity of the primary sensory cortices to external stimuli is preserved at the sedation level of anesthesia.The allosteric modulation of GABA A Rs by the general anesthetics disrupts the normal physiologic circuits, which require precise timing of GABA-ergic input.The GABA A Rs are involved in mediating some of the standard components of general anesthesia: hypnosis, depression of spinal reflexes, and amnesia. 38However, the contribution of GABA A Rs in mediating immobility and analgesia is less clear.Different classes of anesthetics can have differing effects on these pathways.

Functional Effect on Synaptic Phasic Inhibition
Spill Over Inhibition Etomidate, 39 propofol, 40 the barbiturate, pentobarbital, 41 and the neurosteroids tetrahydro deoxycorticosterone (THDOC) and alfaxalone, 42 all prolong neuronal IPSCs decay by phasic inhibition associated with αβγ receptors.The drug effects are studied for desensitization (current reduction during agonist application) and deactivation (current return to baseline after terminating agonist application).Propofol decreases the extent of desensitization of α1β3γ2 and α6β3γ2 receptors, while THDOC and etomidate do not alter desensitization of α1β2/3γ2 receptors.General anesthetics prolong the deactivation of α1β2/3γ2 and α6β3γ2 receptors.Hence, desensitization may contribute to the differences in the apparent maximal intrinsic efficacy at αβγ receptors.

Functional Effect on Spillover Inhibition
The GABA spills over from the synapse to activate extrasynaptic or perisynaptic GABA A Rs at relatively high frequencies of presynaptic stimulation, producing IPSCs.Pentobarbital, propofol, the steroidal anesthetic alfaxalone, and etomidate are known to act as positive allosteric modulators of both synaptic GABA A Rs and extrasynaptic d -GABA A Rs, and they are predicted to enhance "spillover" inhibition.In contrast, benzodiazepines, such as diazepam or midazolam, do not affect d-GABA A Rs and, therefore, are predicted to have only a modest influence on "spillover" inhibition. 43(►Table 5)

Effects of General Anesthetics on GABA A Receptor
Barbiturates: The direct effect of pentobarbital on the α1β3γ2 GABA A Rs appears biphasic, with maximal currents due to direct agonism and inhibition at higher concentrations via a distinct inhibitory site.The anticonvulsant effect is mediated at the γ þ/β--interfaces on α1β3γ2 GABA A R. The γ þ/β-interface can mediate allosteric channel gating shifts in opposing directions, perhaps depending on the specific orientation of hypnotic and convulsant barbiturates within the site (►Fig.6 B).
Etomidate: Etomidate is a potent stereoselective imidazole ester anesthetic.The GABA A R site of effect for etomidate for multiple effects at synapses containing GABA A Rs differs from the site for the enhancing effect of etomidate on the modulation of GABA-induced chloride currents.The former site lies within the outer third of the transmembrane domain of the GABA A R and is located between subunits.The latter exists within the transmembrane helical bundle of the subunit.Evidence suggests that etomidate binds selectively in the two βþ /α-interfaces of α1β2/3γ GABA A Rs in the transmembrane domain (►Fig.6B).R-(þ)-etomidate positively modulates and directly activates α1β2γ2 receptors about 20-fold more potently than S(-) etomidate. 27tomidate has a more substantial effect on the β3 subunit at GABA A slow synapses than on GABA A fast receptors.Thus, etomidate effects lower-frequency electroencephalogram rhythms (i.e., d and u oscillations) more than higher-frequency activity (i.e., γ oscillations).The amnesic effects of etomidate are mediated through α5-containing receptors forming "tonic" GABA A Rs, but this does not produce the sedative or immobilizing effects.The loss of recall, sedation, loss of consciousness, and surgical immobility effects of etomidate may be mediated by actions on other ion channels and signaling pathways.Etomidate analogs have been developed with selective GABA A effect and avoidance of prolonged adrenocortical suppression.
Propofol: The alkylphenol propofol (2,6, di-isopropyl phenol) has both GABA-potentiating effects and direct effects on GABA A R. The property of direct activation of the GABA receptor by propofol depends on the β subunit, while the modulatory effects were considered to involve α and β subunits.The α, β, and γ subunits contribute to the sensitivity of GABA A R to propofol 44 (►Fig.6 B).Propofol was shown to be less efficacious at β1-containing receptors than at those containing β2 or β3 subunits. 45enzodiazepines: The drugs of the benzodiazepine family, including the newer drugs like remimazolam, bind to the interface between α and γ subunits, while barbiturates bind to the β and γ interface subunit of GABA A R (►Fig.6A).So, there is the additive effect between benzodiazepine and barbiturate and no competitive effect.Benzodiazepines are GABA facilitatory and increase the frequency of chloride ion channel opening, while barbiturates are GABA mimetic and increase the duration of chloride ion opening.
Volatile Anesthetics: Isoflurane, desflurane, and sevoflurane enhance the amplitude and prolong the duration of GABA-mediated synaptic inhibition at low concentrations.At supraclinical concentrations, they can cause "direct activation" by opening the receptor's anion channel even in the absence of GABA.
Ketamine: The primary target site for ketamine is the Nmethyl-D-aspartate (NMDA) receptor, but it also inhibits GABAergic-enhanced conductance arising from α6-containing GABA A Rs. 46 Ketamine has a high affinity for NMDA receptors on the inhibitory GABAergic interneurons.Thus, ketamine may also share the exact hypnotic mechanism as that of the GABAergic anesthetics.

Modulation of GABA A R by Nonanesthetic Drugs
Several nonanesthetic drugs that modulate GABA A positively and negatively are used in the treatment of neurological conditions such as seizures, pain, cognitive dysfunction, and sleep disorders.The drug gabapentin is used to treat partialonset seizures, sleep disorders, and alcohol withdrawal.Its mechanism of action is still unclear; it possibly acts by enhancement of GABA synthesis.Vigabatrin increases the ambient GABA levels by an irreversible block of GABA transaminase and is used to manage refractory complex partial seizures and infantile spasms but has the drawback of visual field loss.Pregabalin enhances the activity of glutamic acid decarboxylase, leading to increased GABA synthesis and higher ambient GABA levels.Pregabalin is used in the management of partial seizures (with or without secondary generalization), neuropathic pain (diabetes, postherpetic neuralgia), and anxiety disorder.Ganaxolone and alphaxalone are the positive allosteric modulators of most GABA A Rs with greater potency at d-GABA A Rs, leading to selective enhancement of the tonic conductance.Ganaxolone is used for catamenial epilepsy management, while alphaxalone is used for anesthetic and long-term sedation in the intensive care unit.

GABA Antagonists
These drugs bind to GABA and inhibit its action, exhibiting convulsant and stimulant effects.They are used to treat the overdose of sedative drugs.They act at the GABA receptor site and are classified as competitive, noncompetitive antagonists and negative allosteric modulators.The details of these drugs are summarized in ►Table 6.

Role of GABA A R in Neurological Conditions
Abnormality in the GABAR function has been implicated in several neurological conditions.

Sleep Disorders
GABA A Rs play a pivotal role in the control of sleep rhythms.The alterations in the dynamics of the thalamo-striatal-cortical network and the alterations in extrasynaptic GABA A R function play a vital role in sleep.The alterations in ambient GABA levels may contribute to the sleep disturbances commonly associated with several neurological disorders, including depression.
Sleep abnormalities are the frequent nonmotor and early symptoms of Parkinson's disease. 47The caudate-putamen of the striatum that is linked to Parkinson's disease also expresses high levels of extrasynaptic α4βd subunit-containing GABA A Rs.In Parkinson's disease, the loss of dopaminergic drive enhances the GABA concentrations in the striatum, and this change may underlie the sleep disruptions associated with Parkinson's disease. 48

Epilepsy
Disturbances in synaptic and extrasynaptic GABA A R function have been implicated in many forms of epilepsy. 49Maintaining appropriate levels of tonic inhibition is vital for controlling neuronal network behavior.d-GABA A Rs are often targeted in the treatment of specific forms of epilepsy, and drugs altering ambient GABA levels in the brain are used as antiepileptics.The mechanism of modulation of GABA by the antiepileptics is tabulated (►Table 7).
All epilepsies do not respond to enhancing tonic inhibition.The defining feature of absence seizures is slow-wave discharges within the thalamocortical network, and this correlates with increased levels of tonic inhibition due to dysfunction of the GABA transporter (GAT-1) and the resulting elevated ambient GABA levels within the thalamus. 50is type of seizure is triggered by enhanced d-GABA A R with drugs like tiagabine and vigabatrin.

Memory and Cognition
Neuronal plasticity is regarded as the mechanism underlying learning and memory.Long-term potentiation at glutamatergic synapses plays a role in neuronal plasticity, and GABAergic inhibition obstructs this plasticity. 51Drugs that modulate tonic inhibition mediated by d-GABA A Rs have potential as novel treatments for Alzheimer's disease or other neurological and psychiatric disorders characterized by deficits in learning, memory, or cognition. 52

Anesthetic-Induced Neurocognitive Changes
Anesthetics are known to produce a prolonged effect on cognition, which is maintained long after the agent is eliminated.Animal studies revealed a persistent increase of the CA1 neuron tonic current mediated by α5-GABA A Rs and an associated decrease in the magnitude of long-term potentiation.The inflammation triggered by surgical trauma, by the anesthetic per se, or both may increase circulating concentrations of IL-1b, which has been shown to increase cell surface expression of a5-GABA A Rs and, consequently, to increase the CA1 tonic current.The anesthetics may act synergistically with IL-1b to enhance the CA1 tonic current mediated by GABA A Rs. 53

Neuroprotection and Recovery of Function after Brain Injury
The adult brain comprises a remarkable structural and functional plasticity, but some barriers may impede its plasticity once a developmental window is closed.Enhanced tonic inhibition has a role in acute neuroprotective quality.The mechanisms involving an enhanced tonic inhibition of GABA A Rs may impede functional plasticity during recovery from cerebral insult. 54Recovery of function following acute cerebral injury may be controlled by the availability of GABA. 55he pathogenesis of several chronic neurological and psychiatric disorders involving neuroplasticity is also attributed to the defects of GABAergic neurotransmission.The mechanism of anesthetic-induced plasticity is not yet entirely known.

Neurosteroids
Neurosteroids are brain-synthesized metabolites of ovarian and adrenal cortical steroid hormones.The glial cells synthesize endogenous neurosteroids like THDOC.d-GABA A Rs are a preferred site of action for neurosteroids, 56 and at physiological concentrations, they selectively enhance tonic currents mediated by αβd receptors. 57The neurosteroid sensitivity of the extrasynaptic GABA A Rs may explain their Enhance GABA catabolism resulting in higher synaptic GABA concentration.Effective in complex-partial seizures Vigabatrin unique permanent suicide inhibitor of GABA transaminase enzyme required for GABA catalysis Enhance GABA catabolism, resulting in higher synaptic GABA concentration.
importance in stress-, ovarian cycle, and pregnancy-related mood disorders.Stress hormones heavily regulate GABA A Rs, and changes in extrasynaptic GABA A R expression are often associated with stress-related disorders.

Future Research Areas
The cryoelectron microscopy of the receptor structure offers critical, novel insights into structure-based drug design that may facilitate the development of better molecules to treat neurological diseases and safer general anesthetics.Neurosteroids binding sites are distinct from etomidate, propofol, and barbiturates binding sites.Neurosteroids enhance GABA A R activation by etomidate and barbiturate and synergize with etomidate in anesthetizing animals. 58The synergism of neurosteroids and anesthetics has the potential for clinical research.Understanding the actions of the anesthetic drugs on the receptors may enable the development of selective anesthetic drugs devoid of adverse effects, such as etomidate, with no adrenocortical effects. 59,60nclusion GABA A , the most prominent fast inhibitory neurotransmitter in the CNS, has various subunits and split variants exhibiting different structures and pharmacology.Various drugs, though bind to the same GABA receptor, produce different effects due to the structural heterogeneity of the receptors, the presence of multiple allosteric binding sites, and a broad range of ligands that can bind to them.Abnormalities of GABA A R have been associated with neurological disorders like epilepsy, neurocognitive disorders, and insomnia.Significant progress in understanding the mechanisms of general anesthetic action at the molecular, cellular, and neural systems levels is essential.

Conflicts of Interest
None declared.

Fig. 1
Fig. 1 Gamma-aminobutyric acid type A receptor (GABA A R) structure: Top view, side view, and composition.(A) Schematic representation of the top view of heteropentamer GABA A R isoform consisting of β2, α1, β2, α1, γ2 subunits arranged counter-clockwise as a ring around a central chloride ion.(B) Schematic representation of the opening of chloride ion channel facilitated by the binding of GABA to GABA A R. (C) Schematic representation of the side view of GABA A R displaying extracellular, transmembrane, and cytosolic domains.Extracellular domain contains a large hydrophilic N-terminal and a small C-terminus.Transmembrane domain comprises four hydrophobic helices (TM: TM1-TM4).TM1 and TM2 helices are connected by a short intracellular loop.TM2 and TM3 helices are connected by a short extracellular loop.TM3 and TM4 helices are connected by a long intracellular phosphorylated loop.

Fig. 4
Fig. 4 Phasic, tonic, and spillover inhibition of thalamic neurons mediated by gamma-aminobutyric acid type A receptors (GABA A R). (A) Phasic inhibition at extrasynaptic GABA A R illustrates rapid phasic inhibition at synapse: it allows the fast and precise presynaptic activity transmission into a postsynaptic signal.(B) Tonic Inhibition at extrasynaptic GABA A R illustrates persistent tonic inhibition at extrasynaptic receptors: it occurs due to activation of extrasynaptic GABA A R sensing the low GABA levels in extracellular space.Sites of action include hippocampal neurons, thalamic relay neurons, and neocortical neurons, crucial in consciousness regulation.(C) Spillover inhibition at extrasynaptic GABA A R. Schematic representation of prolonged "spillover" inhibition: GABA spilling from the synaptic cleft can activate either presynaptic terminals receptors or neighboring synapses on the same or adjacent neurons generating inhibitory postsynaptic currents (IPSC).

Fig. 5
Fig.5Effects of anesthetic drugs on gamma-aminobutyric acid GABA binding site and post-inhibitory GABA A ergic currents.This part illustrates the effects of anesthetic drugs on GABA binding site and postinhibitory GABA A ergic currents.X axis is time and Y axis is current.The figures are not to scale.

Table 1
Types of GABA receptors

Table 2
Pharmacological actions of isoforms of α subunits of GABA A R

Table 3
Pharmacological effects of anesthetic agents mediated by GABA A R subtypes Abbreviation: GABA A R, gamma-aminobutyric acid type A receptor.

Table 4
37fluence of isoforms of α subunits on anesthetic effects of drugs Functional Effects of Anesthetics on Extrasynaptic αβd GABA A R The possibility of extrasynaptic GABA A R site of action of general anesthetics is suggested by enhanced tonic inhibition at hippocampal neurons, thalamic relay neurons, and neocortical neurons by anesthetics like propofol and isoflurane.37Thus,both αβd and αβγ receptors are targets for several general anesthetics.General anesthetics such as barbiturates, benzodiazepines, propofol, and etomidate have been shown to induce changes in GABA-dependent receptor activation mediated by αβγ and αβd receptors.The application of general anesthetics increases the mean channel open time by inducing long-lived open states in the GABA A Rs. General anesthetics at high concentrations also directly activate αβd receptors.

Table 5
The effects of anesthetic drugs on phasic, tonic, and spillover inhibition

Table 6
GABA antagonistsDrugs that potentiate GABA A R currents, such as benzodiazepines and zolpidem, are the mainstay in the treatment of insomnia.The problems of producing tolerance, addiction, and withdrawal prompt the search for more refined drug interventions; d-selective GABA A Rs such as gaboxadol have failed phase III clinical trials as an alternative to benzodiazepines for sleep promotion due to side effects such as hallucinations and disorientation.More potent d-GABA A R selective agonists are under development.

Table 7
GABA receptor modulation by antiepilepticsBarbituratesProlong the open time of the chloride channel burst opening.Effective in GTCSValproateEnhances sodium channel inactivation and reduction in both T-type Ca 2þ channel currents and release of gamma-hydroxybutyric acid.Effective in partial onset and absence seizures Tiagabine Inhibit GABA reuptake into neurons and glia through presynaptic membrane.