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GABAA receptor

From Wikipedia, the free encyclopedia
(Redirected from GABA-A)
Structure of the GABAA receptor (α1β1γ2S: PDB: 6DW1). Top: side view of the GABAA receptor embedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABAA nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).
Schematic structure of the GABAA receptor. Left: GABAA monomeric subunit embedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices (1–4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABAA receptor) is depicted as a yellow line. Right: Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS).[1] Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−
) and, to a lesser extent, bicarbonate ions (HCO−
3).[2][3]

GABAAR are members of the ligand-gated ion channel receptor superfamily, which is a chloride channel family with a dozen or more heterotetrametric subtypes and 19 distinct subunits. These subtypes have distinct brain regional and subcellular localization, age-dependent expression, and the ability to undergo plastic alterations in response to experience, including drug exposure.[4]

GABAAR is not just the target of agonist depressants and antagonist convulsants, but most GABAAR medicines also act at additional (allosteric) binding sites on GABAAR proteins. Some sedatives and anxiolytics, such as benzodiazepines and related medicines, act on GABAAR subtype-dependent extracellular domain sites. Alcohols and neurosteroids, among other general anesthetics, act at GABAAR subunit-interface transmembrane locations. High anesthetic dosages of ethanol act on GABAAR subtype-dependent transmembrane domain locations. Ethanol acts at GABAAR subtype-dependent extracellular domain locations at low intoxication concentrations. Thus, GABAAR subtypes have pharmacologically distinct receptor binding sites for a diverse range of therapeutically significant neuropharmacological drugs.[4]

Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl−
 will flow into the cell.[5] This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (−100 mV).

The active site of the GABAA receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline.[6] The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, alcohol (ethanol),[7] inhaled anaesthetics, kavalactones, cicutoxin, and picrotoxin, among others.[8]

Much like the GABAA receptor, the GABAB receptor is an obligatory heterodimer consisting of GABAB1 and GABAB2 subunits. These subunits include an extracellular Venus Flytrap domain (VFT) and a transmembrane domain containing seven α-helices (7TM domain). These structural components play a vital role in intricately modulating neurotransmission and interactions with drugs. [9]

Target for benzodiazepines

[edit]

The ionotropic GABAA receptor protein complex is also the molecular target of the benzodiazepine class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor site on the protein complex as does the endogenous ligand GABA (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABAA receptors.[10][11] While the majority of GABAA receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABAA receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines,[12] but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABAA receptors. As a result, the IUPHAR has recommended that the terms "BZ receptor", "GABA/BZ receptor" and "omega receptor" no longer be used and that the term "benzodiazepine receptor" be replaced with "benzodiazepine site".[13] Benzodiazepines like diazepam and midazolam act as positive allosteric modulators for GABAA receptors. When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation.[14]

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.[15]

Different benzodiazepines have different affinities for GABAA receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABAA receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity.[16] Anticonvulsant effects can be produced by agonists acting at any of the GABAA subtypes, but current research in this area is focused mainly on producing α2-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.

The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor, and also produces different effects on binding,[17] with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound.[18] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.[19]

Also note that some GABAA agonists such as muscimol and gaboxadol do bind to the same site on the GABAA receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.

Structure and function

[edit]
Schematic diagram of a GABAA receptor protein ((α1)2(β2)2(γ2)) which illustrates the five combined subunits that form the protein, the chloride (Cl−
) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site[20]
Side view of the EM structure of the α1β3γ2 GABAA receptor. GABA and the anaesthetic etomidate are coloured magenta. Subunits in different colours. One alpha and one beta subunit is hidden. Green chloride ions illustrated in the channel pore.[21]

Structural understanding of the GABAA receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates.[22][23][24] The much sought structure of a GABAA receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABAA receptor.[25] Whilst this was a major development, the majority of GABAA receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site. This was finally elucidated in 2018 by the publication of a high resolution cryo-EM structure of rat α1β1γ2S receptor[15] and human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.[26]

GABAA receptors are pentameric transmembrane receptors which consist of five subunits arranged around a central pore. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the membrane of its neuron, usually localized at a synapse, postsynaptically. However, some isoforms may be found extrasynaptically.[27] When vesicles of GABA are released presynaptically and activate the GABA receptors at the synapse, this is known as phasic inhibition. However, the GABA escaping from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons (a phenomenon termed 'spillover') in addition to the constant, low GABA concentrations in the extracellular space results in persistent activation of the GABAA receptors known as tonic inhibition.[28]

The ligand GABA is the endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride anions (Cl−
) and, to a lesser extent, bicarbonate ions (HCO−
3) to pass down their electrochemical gradient. The binding site to GABA is about 80Å away from the narrowest part of the ion channel. Recent computational studies have suggested an allosteric mechanism whereby GABA binding leads to ion channel opening.[29] Because the reversal potential for chloride in most mature neurons is close to or more negative than the resting membrane potential, activation of GABAA receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. The net effect therefore typically inhibitory, reducing the activity of the neuron, although depolarizing currents have been observed in response to GABA in immature neurons in early development. This effect during development is due to a modified Cl−
 gradient wherein the anions leave the cells through the GABAA receptors, since their intracellular chlorine concentration is higher than the extracellular.[30] The difference in extracellular chlorine anion concentration is presumed to be due to the higher activity of chloride transporters, such as NKCC1, transporting chloride into cells which are present early in development, whereas, for instance, KCC2 transports chloride out of cells and is the dominant factor in establishing the chloride gradient later in development. These depolarization events have shown to be key in neuronal development.[31] In the mature neuron, the GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).[32][33] The endogenous ligand that binds to the benzodiazepine site is inosine.[34]

Proper developmental, neuronal cell-type-specific, and activity-dependent GABAergic transmission control is required for nearly all aspects of CNS function.[1]

It has been proposed that the GABAergic system is disrupted in numerous neurodevelopmental diseases, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and that it is a crucial potential target for therapeutic intervention.[35]

Subunits

[edit]

GABAA receptors are members of the large pentameric ligand gated ion channel (previously referred to as "Cys-loop" receptors) super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT3 receptor. There are numerous subunit isoforms for the GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.[36]

In humans, the units are as follows:

There are three ρ units (GABRR1, GABRR2, GABRR3); however, these do not coassemble with the classical GABAA units listed above,[37] but rather homooligomerize to form GABAA-ρ receptors (formerly classified as GABAC receptors but now this nomenclature has been deprecated[38]).

Combinatorial arrays

[edit]

Given the large number of GABAA receptors, a great diversity of final pentameric receptor subtypes is possible. Methods to produce cell-based laboratory access to a greater number of possible GABAA receptor subunit combinations allow teasing apart of the contribution of specific receptor subtypes and their physiological and pathophysiological function and role in the CNS and in disease.[39]

Distribution

[edit]

GABAA receptors are responsible for most of the physiological activities of GABA in the central nervous system, and the receptor subtypes vary significantly. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. The minimal requirement to produce a GABA-gated ion channel is the inclusion of an α and a β subunit.[40] The most common GABAA receptor is a pentamer comprising two α's, two β's, and a γ (α2β2γ). In neurons themselves, the type of GABAA receptor subunits and their densities can vary between cell bodies and dendrites.[41] Benzodiazepines and barbiturates amplify the inhibitory effects mediated by the GABAA receptor.[42] GABAA receptors can also be found in other tissues, including leydig cells, placenta, immune cells, liver, bone growth plates and several other endocrine tissues. Subunit expression varies between 'normal' tissue and malignancies, as GABAA receptors can influence cell proliferation.[43]

Distribution of Receptor Types[44]
Isoform Synaptic/Extrasynaptic Anatomical location
α1β3γ2S Both Widespread
α2β3γ2S Both Widespread
α3β3γ2S Both Reticular thalamic nucleus
α4β3γ2S Both Thalamic relay cells
α5β3γ2S Both Hippocampal pyramidal cells
α6β3γ2S Both Cerebellar granule cells
α1β2γ2S Both Widespread, most abundant
α4β3δ Extrasynaptic Thalamic relay cells
α6β3δ Extrasynaptic Cerebellar granule cells
α1β2 Extrasynaptic Widespread
α1β3 Extrasynaptic Thalamus, hypothalamus
α1β2δ Extrasynaptic Hippocampus
α4β2δ Extrasynaptic Hippocampus, Prefrontal cortex
α3β3θ Extrasynaptic Hypothalamus
α3β3ε Extrasynaptic Hypothalamus

Ligands

[edit]
GABAA receptor and where various ligands bind.

A number of ligands have been found to bind to various sites on the GABAA receptor complex and modulate it besides GABA itself.[which?] A ligand can possess one or more properties of the following types. Unfortunately the literature often does not distinguish these types properly.

Types

[edit]
GABA bound at its orthosteric site in the beta-alpha interface of an α1β2γ2 GABAA receptor. H-atoms hidden.
  • Orthosteric agonists and antagonists: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site). Agonists activate the receptor, resulting in increased Cl−
     conductance. Antagonists, though they have no effect on their own, compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl−
     conductance.
  • First order allosteric modulators: bind to allosteric sites on the receptor complex and affect it either in a positive (PAM), negative (NAM) or neutral/silent (SAM) manner, causing increased or decreased efficiency of the main site and therefore an indirect increase or decrease in Cl−
     conductance. SAMs do not affect the conductance, but occupy the binding site.
  • Second order modulators: bind to an allosteric site on the receptor complex and modulate the effect of first order modulators.
  • Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner.[45]
  • Non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block Cl−
     conductance through the ion channel.

Examples

[edit]

Effects

[edit]

Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. Some such as muscimol and the z-drugs may also be hallucinogenic.[citation needed] Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion.[citation needed] Some of the subtype-selective negative allosteric modulators such as α5IA are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other GABAergic drugs.[59] Advances in molecular pharmacology and genetic manipulation of rat genes have revealed that distinct subtypes of the GABAA receptor mediate certain parts of the anaesthetic behavioral repertoire.[60]

Novel drugs

[edit]

A useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABAA receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABAA receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects.[61] Few subtype selective ligands have gone into clinical use as yet, with the exception of zolpidem which is reasonably selective for α1, but several more selective compounds are in development such as the α3-selective drug adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including:

Diazepam is a benzodiazepine medication that is FDA approved for the treatment of anxiety disorders, the short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, the management of certain refractory epileptic patients, and as an adjunct in severe recurrent convulsive seizures and status epilepticus.[62]

  • CL-218,872 (highly α1-selective agonist)
  • bretazenil (subtype-selective partial agonist)
  • imidazenil and L-838,417 (both partial agonists at some subtypes, but weak antagonists at others)
  • QH-ii-066 (full agonist highly selective for α5 subtype)
  • α5IA (selective inverse agonist for α5 subtype)
  • SL-651,498 (full agonist at α2 and α3 subtypes, and as a partial agonist at α1 and α5
  • 3-acyl-4-quinolones: selective for α1 over α3[63]

Paradoxical reactions

[edit]

There are multiple indications that paradoxical reactions upon — for example — benzodiazepines, barbiturates, inhalational anesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see images above) can be altered in such a way that for example the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2–3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.[64][65][66][67]

See also

[edit]

References

[edit]
  1. ^ a b Luscher B, Fuchs T, Kilpatrick CL (May 2011). "GABAA receptor trafficking-mediated plasticity of inhibitory synapses". Neuron. 70 (3): 385–409. doi:10.1016/j.neuron.2011.03.024. PMC 3093971. PMID 21555068.
  2. ^ Folkman, Susan. (2011). The Oxford handbook of stress, health, and coping. Oxford: Oxford University Press. ISBN 978-0-19-537534-3. OCLC 540015689.
  3. ^ Kaila K, Voipio J (18 November 1987). "Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance". Nature. 330 (6144): 163–5. Bibcode:1987Natur.330..163K. doi:10.1038/330163a0. PMID 3670401. S2CID 4330077.
  4. ^ a b Olsen RW (July 2018). "GABAA receptor: Positive and negative allosteric modulators". Neuropharmacology. 136 (Pt A): 10–22. doi:10.1016/j.neuropharm.2018.01.036. PMC 6027637. PMID 29407219.
  5. ^ Kandel ER, Schwartz JH, Jessell TM, Siegelbaum S, Hudspeth AJ, Mack S (eds.). Principles of neural science (5th ed.). McGraw-Hill. ISBN 978-1-283-65624-5. OCLC 919404585.
  6. ^ Chua HC, Chebib M (2017). "GABA a Receptors and the Diversity in their Structure and Pharmacology". GABAA Receptors and the Diversity in their Structure and Pharmacology. Advances in Pharmacology. Vol. 79. pp. 1–34. doi:10.1016/bs.apha.2017.03.003. ISBN 978-0-12-810413-2. PMID 28528665. S2CID 41704867.
  7. ^ Santhakumar V, Wallner M, Otis TS (May 2007). "Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition". Alcohol. 41 (3): 211–221. doi:10.1016/j.alcohol.2007.04.011. PMC 2040048. PMID 17591544.
  8. ^ Johnston GA (1996). "GABAA receptor pharmacology". Pharmacology & Therapeutics. 69 (3): 173–198. doi:10.1016/0163-7258(95)02043-8. PMID 8783370.
  9. ^ Evenseth LS, Gabrielsen M, Sylte I (July 2020). "The GABAB Receptor-Structure, Ligand Binding and Drug Development". Molecules. 25 (13): 3093. doi:10.3390/molecules25133093. PMC 7411975. PMID 32646032.
  10. ^ Sigel E (August 2002). "Mapping of the benzodiazepine recognition site on GABA(A) receptors". Current Topics in Medicinal Chemistry. 2 (8): 833–9. doi:10.2174/1568026023393444. PMID 12171574.
  11. ^ Akabas MH (2004). GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures. International Review of Neurobiology. Vol. 62. pp. 1–43. doi:10.1016/S0074-7742(04)62001-0. ISBN 978-0-12-366862-2. PMID 15530567.
  12. ^ Derry JM, Dunn SM, Davies M (March 2004). "Identification of a residue in the gamma-aminobutyric acid type A receptor alpha subunit that differentially affects diazepam-sensitive and -insensitive benzodiazepine site binding". Journal of Neurochemistry. 88 (6): 1431–8. doi:10.1046/j.1471-4159.2003.02264.x. PMID 15009644. S2CID 83817337.
  13. ^ Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (June 1998). "International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function". Pharmacological Reviews. 50 (2): 291–313. PMID 9647870.
  14. ^ Gidal B, Detyniecki K (September 2022). "Rescue therapies for seizure clusters: Pharmacology and target of treatments". Epilepsia. 63 (Suppl 1): S34–S44. doi:10.1111/epi.17341. PMC 9543841. PMID 35999174.
  15. ^ a b Phulera S, Zhu H, Yu J, Claxton DP, Yoder N, Yoshioka C, Gouaux E (July 2018). "Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA". eLife. 7: e39383. doi:10.7554/eLife.39383. PMC 6086659. PMID 30044221.
  16. ^ Atack JR (August 2003). "Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site". Current Drug Targets. CNS and Neurological Disorders. 2 (4): 213–232. doi:10.2174/1568007033482841. PMID 12871032.
  17. ^ Hanson SM, Czajkowski C (March 2008). "Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor". The Journal of Neuroscience. 28 (13): 3490–9. doi:10.1523/JNEUROSCI.5727-07.2008. PMC 2410040. PMID 18367615.
  18. ^ Twyman RE, Rogers CJ, Macdonald RL (March 1989). "Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital". Annals of Neurology. 25 (3): 213–220. doi:10.1002/ana.410250302. hdl:2027.42/50330. PMID 2471436. S2CID 72023197.
  19. ^ Hanson SM, Czajkowski C (March 2008). "Structural mechanisms underlying benzodiazepine modulation of the GABA(A) receptor". J Neurosci. 28 (13): 3490–9. doi:10.1523/JNEUROSCI.5727-07.2008. PMC 2410040. PMID 18367615.
  20. ^ Richter L, de Graaf C, Sieghart W, Varagic Z, Mörzinger M, de Esch IJ, Ecker GF, Ernst M (March 2012). "Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands". Nature Chemical Biology. 8 (5): 455–464. doi:10.1038/nchembio.917. PMC 3368153. PMID 22446838.
  21. ^ Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, et al. (September 2020). "Shared structural mechanisms of general anaesthetics and benzodiazepines". Nature. 585 (7824): 303–308. doi:10.1038/s41586-020-2654-5. PMC 7486282. PMID 32879488.
  22. ^ Ernst M, Bruckner S, Boresch S, Sieghart W (November 2005). "Comparative models of GABAA receptor extracellular and transmembrane domains: important insights in pharmacology and function" (PDF). Molecular Pharmacology. 68 (5): 1291–1300. doi:10.1124/mol.105.015982. PMID 16103045. S2CID 15678338. Archived from the original (PDF) on 2019-03-03.
  23. ^ Vijayan RS, Trivedi N, Roy SN, Bera I, Manoharan P, Payghan PV, Bhattacharyya D, Ghoshal N (November 2012). "Modeling the closed and open state conformations of the GABA(A) ion channel--plausible structural insights for channel gating". Journal of Chemical Information and Modeling. 52 (11): 2958–2969. doi:10.1021/ci300189a. PMID 23116339.
  24. ^ Mokrab Y, Bavro V, Mizuguchi K, Todorov NP, Martin IL, Dunn SM, Chan SL, Chau PL (November 2007). "Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor". Journal of Molecular Graphics and Modelling. 26 (4): 760–774. doi:10.1016/j.jmgm.2007.04.012. PMID 17544304.
  25. ^ Miller PS, Aricescu AR (August 2014). "Crystal structure of a human GABAA receptor". Nature. 512 (7514): 270–275. Bibcode:2014Natur.512..270M. doi:10.1038/nature13293. PMC 4167603. PMID 24909990.
  26. ^ Zhu S, Noviello CM, Teng J, Walsh RM, Kim JJ, Hibbs RE (July 2018). "Structure of a human synaptic GABAA receptor". Nature. 559 (7712): 67–72. Bibcode:2018Natur.559...67Z. doi:10.1038/s41586-018-0255-3. PMC 6220708. PMID 29950725.
  27. ^ Wei W, Zhang N, Peng Z, Houser CR, Mody I (November 2003). "Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus". The Journal of Neuroscience. 23 (33): 10650–61. doi:10.1523/JNEUROSCI.23-33-10650.2003. PMC 6740905. PMID 14627650.
  28. ^ Farrant M, Nusser Z (March 2005). "Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors". Nature Reviews. Neuroscience. 6 (3): 215–29. doi:10.1038/nrn1625. PMID 15738957. S2CID 18552767.
  29. ^ Várnai C, Irwin BW, Payne MC, Csányi G, Chau PL (July 2020). "Functional movements of the GABA type A receptor". Physical Chemistry Chemical Physics. 22 (28): 16023–16031. Bibcode:2020PCCP...2216023V. doi:10.1039/D0CP01128B. PMID 32633279.
  30. ^ Ben-Ari Y, Cherubini E, Corradetti R, Gaiarsa JL (September 1989). "Giant synaptic potentials in immature rat CA3 hippocampal neurones". The Journal of Physiology. 416: 303–325. doi:10.1113/jphysiol.1989.sp017762. PMC 1189216. PMID 2575165.
  31. ^ Spitzer NC (March 2010). "How GABA generates depolarization". The Journal of Physiology. 588 (Pt 5): 757–758. doi:10.1113/jphysiol.2009.183574. PMC 2834934. PMID 20194137.
  32. ^ 16. GABA and Glycine 1999
  33. ^ Chen K, Li HZ, Ye N, Zhang J, Wang JJ (October 2005). "Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro". Brain Research Bulletin. 67 (4): 310–318. doi:10.1016/j.brainresbull.2005.07.004. PMID 16182939. S2CID 6433030.
  34. ^ Yarom M, Tang XW, Wu E, Carlson RG, Vander Velde D, Lee X, Wu J (2016-08-01). "Identification of inosine as an endogenous modulator for the benzodiazepine binding site of the GABAA receptors". Journal of Biomedical Science. 5 (4): 274–280. doi:10.1007/bf02255859. PMID 9691220.
  35. ^ Braat S, Kooy RF (June 2015). "The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders". Neuron. 86 (5): 1119–30. doi:10.1016/j.neuron.2015.03.042. PMID 26050032.
  36. ^ Cossart R, Bernard C, Ben-Ari Y (February 2005). "Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies". Trends in Neurosciences. 28 (2): 108–115. doi:10.1016/j.tins.2004.11.011. PMID 15667934. S2CID 1424286.
  37. ^ Enz R, Cutting GR (May 1998). "Molecular composition of GABAC receptors". Vision Research. 38 (10): 1431–1441. doi:10.1016/S0042-6989(97)00277-0. PMID 9667009. S2CID 14457042.
  38. ^ Olsen RW, Sieghart W (January 2009). "GABA A receptors: subtypes provide diversity of function and pharmacology". Neuropharmacology. 56 (1): 141–148. doi:10.1016/j.neuropharm.2008.07.045. PMC 3525320. PMID 18760291.
  39. ^ Shekdar K, Langer J, Venkatachalan S, Schmid L, Anobile J, Shah P, et al. (March 2021). "Cell engineering method using fluorogenic oligonucleotide signaling probes and flow cytometry". Biotechnology Letters. 43 (5): 949–958. doi:10.1007/s10529-021-03101-5. PMC 7937778. PMID 33683511.
  40. ^ Connolly CN, Krishek BJ, McDonald BJ, Smart TG, Moss SJ (January 1996). "Assembly and cell surface expression of heteromeric and homomeric gamma-aminobutyric acid type A receptors". The Journal of Biological Chemistry. 271 (1): 89–96. doi:10.1074/jbc.271.1.89. PMID 8550630.
  41. ^ Lorenzo LE, Russier M, Barbe A, Fritschy JM, Bras H (September 2007). "Differential organization of gamma-aminobutyric acid type A and glycine receptors in the somatic and dendritic compartments of rat abducens motoneurons". The Journal of Comparative Neurology. 504 (2): 112–126. doi:10.1002/cne.21442. PMID 17626281. S2CID 26123520.
  42. ^ Macdonald RL, Kelly KM (1995). "Antiepileptic drug mechanisms of action". Epilepsia. 36 (Suppl 2): S2–12. doi:10.1111/j.1528-1157.1995.tb05996.x. hdl:2027.42/66291. PMID 8784210.
  43. ^ Hoeve, A.L. ten (2012). GABA receptors and the immune system (PDF) (Thesis). Utrecht University. hdl:20.500.12932/10140.
  44. ^ Mortensen M, Patel B, Smart TG (January 2011). "GABA Potency at GABA(A) Receptors Found in Synaptic and Extrasynaptic Zones". Frontiers in Cellular Neuroscience. 6: 1. doi:10.3389/fncel.2012.00001. PMC 3262152. PMID 22319471.
  45. ^ Haseneder R, Rammes G, Zieglgänsberger W, Kochs E, Hapfelmeier G (September 2002). "GABA(A) receptor activation and open-channel block by volatile anaesthetics: a new principle of receptor modulation?". European Journal of Pharmacology. 451 (1): 43–50. doi:10.1016/S0014-2999(02)02194-5. PMID 12223227.
  46. ^ a b Mori M, Gähwiler BH, Gerber U (February 2002). "Beta-alanine and taurine as endogenous agonists at glycine receptors in rat hippocampus in vitro". The Journal of Physiology. 539 (Pt 1): 191–200. doi:10.1113/jphysiol.2001.013147. PMC 2290126. PMID 11850512.
  47. ^ a b Horikoshi T, Asanuma A, Yanagisawa K, Anzai K, Goto S (September 1988). "Taurine and beta-alanine act on both GABA and glycine receptors in Xenopus oocyte injected with mouse brain messenger RNA". Brain Research. 464 (2): 97–105. doi:10.1016/0169-328x(88)90002-2. PMID 2464409.
  48. ^ Dn, Stephens; Hh, Schneider; W, Kehr; Js, Andrews; Kj, Rettig; L, Turski; R, Schmiechen; Jd, Turner; Lh, Jensen; En, Petersen (April 1990). "Abecarnil, a metabolically stable, anxioselective beta-carboline acting at benzodiazepine receptors". The Journal of Pharmacology and Experimental Therapeutics. 253 (1): 334–343. ISSN 0022-3565. PMID 1970361.
  49. ^ Maleeva, Galyna; Nin-Hill, Alba; Wirth, Ulrike; Rustler, Karin; Ranucci, Matteo; Opar, Ekin; Rovira, Carme; Bregestovski, Piotr; Zeilhofer, Hanns Ulrich; König, Burkhard; Alfonso-Prieto, Mercedes; Gorostiza, Pau (2024-10-09). "Light-Activated Agonist-Potentiator of GABA A Receptors for Reversible Neuroinhibition in Wildtype Mice". Journal of the American Chemical Society. doi:10.1021/jacs.4c08446. ISSN 0002-7863. PMC 11503767. PMID 39383450.
  50. ^ Hunter, A (2006). "Kava (Piper methysticum) back in circulation". Australian Centre for Complementary Medicine. 25 (7): 529.
  51. ^ (a) Herd MB, Belelli D, Lambert JJ (October 2007). "Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors". Pharmacology & Therapeutics. 116 (1): 20–34. arXiv:1607.02870. doi:10.1016/j.pharmthera.2007.03.007. PMID 17531325.
    (b) Hosie AM, Wilkins ME, da Silva HM, Smart TG (November 2006). "Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites". Nature. 444 (7118): 486–9. Bibcode:2006Natur.444..486H. doi:10.1038/nature05324. PMID 17108970. S2CID 4382394.
    (c) Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (September 2006). "Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis". Proceedings of the National Academy of Sciences of the United States of America. 103 (39): 14602–7. Bibcode:2006PNAS..10314602A. doi:10.1073/pnas.0606544103. PMC 1600006. PMID 16984997.
    (d) Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (December 2005). "Neurosteroid access to the GABAA receptor". The Journal of Neuroscience. 25 (50): 11605–13. doi:10.1523/JNEUROSCI.4173-05.2005. PMC 6726021. PMID 16354918.
    (e) Belelli D, Lambert JJ (July 2005). "Neurosteroids: endogenous regulators of the GABA(A) receptor". Nature Reviews. Neuroscience. 6 (7): 565–575. doi:10.1038/nrn1703. PMID 15959466. S2CID 12596378.
    (f) Pinna G, Costa E, Guidotti A (June 2006). "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology. 186 (3): 362–372. doi:10.1007/s00213-005-0213-2. PMID 16432684. S2CID 7799814.
    (g) Dubrovsky BO (February 2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 29 (2): 169–192. doi:10.1016/j.pnpbp.2004.11.001. PMID 15694225. S2CID 36197603.
    (h) Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends in Endocrinology and Metabolism. 13 (1): 35–43. doi:10.1016/S1043-2760(01)00503-3. PMID 11750861. S2CID 11605131.
    (i) Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (May 1990). "Neurosteroids act on recombinant human GABAA receptors". Neuron. 4 (5): 759–765. doi:10.1016/0896-6273(90)90202-Q. PMID 2160838. S2CID 12626366.
    (j) Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (May 1986). "Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor". Science. 232 (4753): 1004–7. Bibcode:1986Sci...232.1004D. doi:10.1126/science.2422758. PMID 2422758.
    (k) Reddy DS, Rogawski MA (2012). "Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy". In Noebels JL, Avoli M, Rogawski MA, et al. (eds.). Jasper's Basic Mechanisms of the Epilepsies [Internet] (4th ed.). National Center for Biotechnology Information (US). PMID 22787590. NBK98218.
  52. ^ Toraskar M, Singh PR, Neve S (2010). "STUDY OF GABAERGIC AGONISTS" (PDF). Deccan Journal of Pharmacology. 1 (2): 56–69. Archived from the original (PDF) on 2013-10-16. Retrieved 2013-02-12.
  53. ^ Fisher JL (January 2009). "The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator". Neuropharmacology. 56 (1): 190–7. doi:10.1016/j.neuropharm.2008.06.004. PMC 2665930. PMID 18585399.
  54. ^ Boldyreva AA (October 2005). "Lanthanum potentiates GABA-activated currents in rat pyramidal neurons of CA1 hippocampal field". Bulletin of Experimental Biology and Medicine. 140 (4): 403–5. doi:10.1007/s10517-005-0503-z. PMID 16671565. S2CID 13179025.
  55. ^ He Y, Benz A, Fu T, Wang M, Covey DF, Zorumski CF, Mennerick S (February 2002). "Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function". Neuropharmacology. 42 (2): 199–209. doi:10.1016/s0028-3908(01)00175-7. PMID 11804616. S2CID 24194421.
  56. ^ Lau, B. K.; Karim, S.; Goodchild, A. K.; Vaughan, C. W.; Drew, G. M. (2014). "Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons". British Journal of Pharmacology. 171 (11): 2803–13. doi:10.1111/bph.12602. PMC 4243856. PMID 24460753.
  57. ^ Hosie AM, Dunne EL, Harvey RJ, Smart TG (April 2003). "Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity". Nature Neuroscience. 6 (4): 362–9. doi:10.1038/nn1030. PMID 12640458. S2CID 24096465.
  58. ^ Campbell EL, Chebib M, Johnston GA (October 2004). "The dietary flavonoids apigenin and (-)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA(A) receptors". Biochemical Pharmacology. Six Decades of GABA. 68 (8): 1631–8. doi:10.1016/j.bcp.2004.07.022. PMID 15451406.
  59. ^ Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR (March 2006). "An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1335–45. doi:10.1124/jpet.105.092320. PMID 16326923. S2CID 6410599. Archived from the original (PDF) on 2019-02-20.
  60. ^ Weir CJ, Mitchell SJ, Lambert JJ (December 2017). "Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics". Br J Anaesth. 119 (suppl_1): i167–i175. doi:10.1093/bja/aex369. PMID 29161398.
  61. ^ Da Settimo F, Taliani S, Trincavelli ML, Montali M, Martini C (2007). "GABA A/Bz receptor subtypes as targets for selective drugs". Current Medicinal Chemistry. 14 (25): 2680–2701. doi:10.2174/092986707782023190. PMID 17979718.
  62. ^ Sieghart W, Ramerstorfer J, Sarto-Jackson I, Varagic Z, Ernst M (May 2012). "A novel GABA(A) receptor pharmacology: drugs interacting with the α(+) β(-) interface". Br J Pharmacol. 166 (2): 476–85. doi:10.1111/j.1476-5381.2011.01779.x. PMC 3417481. PMID 22074382.
  63. ^ Lager E, Nilsson J, Østergaard Nielsen E, Nielsen M, Liljefors T, Sterner O (July 2008). "Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABA(A) receptors". Bioorganic & Medicinal Chemistry. 16 (14): 6936–48. doi:10.1016/j.bmc.2008.05.049. PMID 18541432.
  64. ^ Robin C, Trieger N (2002). "Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature". Anesthesia Progress. 49 (4): 128–32. PMC 2007411. PMID 12779114.
  65. ^ Paton C (2002). "Benzodiazepines and disinhibition: a review" (PDF). Psychiatric Bulletin. 26 (12). Royal College of Psychiatrists: 460–2. doi:10.1192/pb.26.12.460.
  66. ^ Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, et al. (February 2014). "Allopregnanolone and mood disorders". Progress in Neurobiology. 113: 88–94. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486. S2CID 207407084.
  67. ^ Brown EN, Lydic R, Schiff ND (December 2010). Schwartz RS (ed.). "General anesthesia, sleep, and coma". The New England Journal of Medicine. 363 (27): 2638–50. doi:10.1056/NEJMra0808281. PMC 3162622. PMID 21190458.

Further reading

[edit]
  • Olsen RW, DeLorey TM (1999). "16. GABA and Glycine". In Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD (eds.). Basic neurochemistry: molecular, cellular, and medical aspects (6th ed.). Philadelphia: Lippincott-Raven. ISBN 978-0-397-51820-3. NBK28090.
  • Olsen RW, Betz H (2005). "16. GABA and Glycine". In Siegel GJ, Albers RW, Brady S, Price DD (eds.). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Academic Press. pp. 291–302. ISBN 978-0-12-088397-4.
  • Uusi-Oukari M, Korpi ER (March 2010). "Regulation of GABA(A) receptor subunit expression by pharmacological agents". Pharmacological Reviews. 62 (1): 97–135. doi:10.1124/pr.109.002063. PMID 20123953. S2CID 12202117.
  • Rudolph U (2015). Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler. Academic Press, Elsevier. ISBN 978-0-12-802660-1.
[edit]
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