GABAA受容体、GABAAレセプター、GABA-A受容体、GABA-Aレセプター

関: GABA-A receptor

WordNet

a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

PrepTutorEJDIC

=sense organ / 受信装置

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/05/21 16:57:52」(JST)

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Structure of the nicotinic acetylcholine receptor (nAchR: PDB 2BG9) which is very similar to the GABA_A receptor.^[1]^[2]^[3] Top: side view of the nAchR imbedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABA_A 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 GABA_A receptor. Left: GABA_A monomeric subunit imbedded 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 GABA_A 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 GABA_A receptor (GABA_AR) 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. Upon activation, the GABA_A receptor selectively conducts Cl⁻ through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring. The reversal potential of the GABA_A-mediated IPSP in normal solution is −70 mV, contrasting the GABA_B IPSP.

The active site of the GABA_A receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline. 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, barbiturates, ethanol,^[4] neuroactive steroids, inhaled anaesthetics, and picrotoxin, among others.^[5]

GABA_A receptors occur in all organisms that have a nervous system. To a limited extent the receptors can be found in non-neuronal tissues. Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.

Target for benzodiazepines

The ionotropic GABA_A 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 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 GABA_A receptors (see figure to the right).^[6]^[7] While the majority of GABA_A receptors (those containing α₁-, α₂-, α₃-, or α₅-subunits) are benzodiazepine sensitive there exists a minority of GABA_A receptors (α₄- or α₆-subunit containing) which are insensitive to classical 1,4-benzodiazepines,^[8] but instead are sensitive to other classes of GABAergic drugs such as the neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABA_A 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".^[9]

In order for GABA_A 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 GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A 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.

Different benzodiazepines have different affinities for GABA_A 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 GABA_A receptors containing α₂ and/or α₃ subunits generally have greater anxiolytic activity.^[10] Anticonvulsant effects can be produced by agonists acting at any of the GABA_A 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 GABA_A receptor, and also produces different effects on binding,^[11] with the benzodiazepines causing bursts of chloride channel opening to occur more often, while the barbiturates cause the duration of bursts of chloride channel opening to become longer.^[12] 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.

Also note that some GABA_A agonists such as muscimol and gaboxadol do bind to the same site on the GABA_A 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

Schematic diagram of a GABA_A 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 (BDZ) allosteric binding site^[1]

The receptor is a pentameric transmembrane receptor that consists 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.^[13] 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⁻) to pass down an electrochemical gradient. Because the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential, activation of GABA_A 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 is typically inhibitory, reducing the activity of the neuron. The GABA_A channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP).^[14]^[15] The endogenous ligand that binds to the benzodiazepine site is inosine.

Subunits

GABA_A receptors are members of the large "Cys-loop" 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 GABA_A receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.^[16]

In humans, the units are as follows:^[17]

six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6)
three βs (GABRB1, GABRB2, GABRB3)
three γs (GABRG1, GABRG2, GABRG3)
as well as a δ (GABRD), an ε (GABRE), a π (GABRP), and a θ (GABRQ)

There are three ρ units (GABRR1, GABRR2, GABRR3), however these do not coassemble with the classical GABA_A units listed above,^[18] but rather homooligomerize to form GABA_A-ρ receptors (formerly classified as GABA_C receptors but now this nomenclature has been deprecated^[19] ).

Five subunits can combine in different ways to form GABA_A channels. The minimal requirement to produce a GABA-gated ion channel is the inclusion of both α and β subunits,^[20] but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α₂β₂γ).^[17]

The receptor binds two GABA molecules,^[21] at the interface between an α and a β subunit.^[17]

Ligands

A number of ligands have been found to bind to various sites on the GABA_A receptor complex and modulate it besides GABA itself.

Types

Agonists: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site) and activate it, resulting in increased Cl⁻ conductance.
Antagonists: bind to the main receptor site but do not activate it. Though they have no effect on their own, antagonists compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl⁻ conductance.
Positive allosteric modulators: bind to allosteric sites on the receptor complex and affect it in a positive manner, causing increased efficiency of the main site and therefore an indirect increase in Cl⁻ conductance.
Negative allosteric modulators: bind to an allosteric site on the receptor complex and affect it in a negative manner, causing decreased efficiency of the main site and therefore an indirect decrease in Cl⁻ conductance.
Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner.^[22]
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

Agonists: GABA, gaboxadol, ibotenic acid, muscimol, progabide, piperidine-4-sulfonic acid (partial agonist).
Antagonists: bicuculline, gabazine.
Positive allosteric modulators: barbiturates, benzodiazepines, carisoprodol, thienodiazepines, ethanol (alcohol), etomidate, glutethimide, kavalactones,^[23] meprobamate, methaqualone, neuroactive steroids,^[24] niacin/niacinamide,^[25] nonbenzodiazepines, propofol, stiripentol,^[26] theanine, valerenic acid, volatile/inhaled anesthetics, and lanthanum.^[27]
Negative allosteric modulators: flumazenil, Ro15-4513, sarmazenil, and zinc.^[28]
Non-competitive channel blockers: cicutoxin, oenanthotoxin, pentylenetetrazol, picrotoxin, thujone, and lindane

Effects

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. Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion. 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.^[29] One particularly new area of development is the interaction of xenon and the GABA_A receptor. Xenon, although expensive to administer at approximately $150/hr, has all the benefits of nitrous oxide, while retaining nootropic effects and decreasing anesthesia time, this has been thought to be an interaction of xenon and the GABA_A receptor.^{[citation needed]}

Novel drugs

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 GABA_A 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 GABA_A receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects.^[30] 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:

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^[31]

Distribution

As GABA_A receptors are responsible for most of the physiological activities of GABA in the central nervous system, subunits are expressed in many parts of the brain. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. Interestingly, GABA_A 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 and GABA_A receptors can influence cell proliferation.^[32]

References

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^ Olsen RW, DeLorey TM (1999). "Chapter 16: GABA and Glycine". In Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD. Basic neurochemistry: molecular, cellular, and medical aspects (Sixth ed.). Philadelphia: Lippincott-Raven. ISBN 0-397-51820-X.
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^ ^a ^b ^c Martin IL and Dunn SMJ. GABA receptors A review of GABA and the receptors to which it binds. Tocris Cookson LTD.
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^ Hunter, A (2006). "Kava (Piper methysticum) back in circulation". Australian Centre for Complementary Medicine 25 (7): 529.
^ (a) Herd MB, Belelli D, Lambert JJ (2007). "Neurosteroid modulation of synaptic and extrasynaptic GABA_A receptors". Pharmacology & Therapeutics 116 (1): 20–34. doi:10.1016/j.pharmthera.2007.03.007. PMID 17531325. ; (b) Hosie AM, Wilkins ME, da Silva HM, Smart TG (2006). "Endogenous neurosteroids regulate GABA_A receptors through two discrete transmembrane sites". Nature 444 (7118): 486–9. doi:10.1038/nature05324. PMID 17108970. ; (c)Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (2006). "Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis". Proc. Natl. Acad. Sci. U.S.A. 103 (39): 14602–7. doi:10.1073/pnas.0606544103. PMC 1600006. PMID 16984997. ; (d) Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (2005). "Neurosteroid access to the GABA_A receptor". J. Neurosci. 25 (50): 11605–13. doi:10.1523/JNEUROSCI.4173-05.2005. PMID 16354918. ; (e) Belelli D, Lambert JJ (2005). "Neurosteroids: endogenous regulators of the GABA_A receptor". Nat. Rev. Neurosci. 6 (7): 565–75. doi:10.1038/nrn1703. PMID 15959466. ; (f) Pinna G, Costa E, Guidotti A (2006). "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology (Berl.) 186 (3): 362–72. doi:10.1007/s00213-005-0213-2. PMID 16432684. ; (g) Dubrovsky BO (2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2): 169–92. doi:10.1016/j.pnpbp.2004.11.001. PMID 15694225. ; (h) Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends Endocrinol. Metab. 13 (1): 35–43. doi:10.1016/S1043-2760(01)00503-3. PMID 11750861. ; (i) Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (1990). "Neurosteroids act on recombinant human GABA_A receptors". Neuron 4 (5): 759–65. doi:10.1016/0896-6273(90)90202-Q. PMID 2160838. ; (j) Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986). "Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor". Science 232 (4753): 1004–7. doi:10.1126/science.2422758. PMID 2422758.
^ Toraskar, Mrunmayee; Pratima R.P. Singh; Shashank Neve (2010). "STUDY OF GABAERGIC AGONISTS". Deccan Journal of Pharmacology 1 (2): 56–69.
^ Fisher JL (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.
^ Boldyreva, A. A. (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.
^ Hosie AM,Dunne EL,Harvey RJ,Smart TG (2003). "Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity". Nat Neurosci. 6 (4): 362–9. doi:10.1038/nn1030. PMID 12640458.
^ 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". J. Pharmacol. Exp. Ther. 316 (3): 1335–45. doi:10.1124/jpet.105.092320. PMID 16326923.
^ Da Settimo F, Taliani S, Trincavelli ML, Montali M, Martini C (2007). "GABA A/Bz receptor subtypes as targets for selective drugs". Curr. Med. Chem. 14 (25): 2680–701. doi:10.2174/092986707782023190. PMID 17979718.
^ 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". Bioorg. Med. Chem. 16 (14): 6936–48. doi:10.1016/j.bmc.2008.05.049. PMID 18541432.
^ ten Hoeve AL (2012). GABA receptors and the immune system. Thesis, Utrecht University

External links

Receptors, GABA-A at the US National Library of Medicine Medical Subject Headings (MeSH)
Olsen RW, DeLorey TM (1999). "Chapter 16: GABA and Glycine". In Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD. Basic neurochemistry: molecular, cellular, and medical aspects (Sixth ed.). Philadelphia: Lippincott-Raven. ISBN 0-397-51820-X.
Olsen RW, Betz H (2005). "Chapter 16: GABA and Glycine". In Siegel GJ, Albers RW, Brady S , Price DD. Basic Neurochemistry: Molecular, Cellular and Medical Aspects (Seventh ed.). Boston: Academic Press. pp. 291–302. ISBN 0-12-088397-X.
Uusi-Oukari M, Korpi ER (2010). Regulation of GABAA Receptor Subunit Expression by Pharmacological Agents. Pharmacological Reviews, pp 97–135. PMID 20123953.

UpToDate Contents

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English Journal

Phenytoin attenuates the hyper-exciting neurotransmission in cultured embryonic cortical neurons.

Chou MY1, Lee CY2, Liou HH3, Pan CY4.
Neuropharmacology.Neuropharmacology.2014 Aug;83:54-61. doi: 10.1016/j.neuropharm.2014.03.012. Epub 2014 Apr 8.
Phenytoin is an effective anti-epileptic drug that inhibits Na(+) channel activities; however, how phenytoin modulates synaptic transmission to soothe epileptic symptoms is not clear. To characterize the effects of phenytoin regulation on neurotransmission, we studied the electrophysical properties
PMID 24721626

Evidence for the participation of peripheral α5 subunit-containing GABAA receptors in GABAA agonists-induced nociception in rats.

Bravo-Hernández M1, Feria-Morales LA2, Torres-López JE3, Cervantes-Durán C4, Delgado-Lezama R5, Granados-Soto V6, Rocha-González HI7.
European journal of pharmacology.Eur J Pharmacol.2014 Jul 5;734:91-7. doi: 10.1016/j.ejphar.2014.03.051. Epub 2014 Apr 12.
The activation of GABAA receptor by γ-amino butyric acid (GABA) in primary afferent fibers produces depolarization. In normal conditions this depolarization causes a reduction in the release of neurotransmitters. Therefore, this depolarization remains inhibitory. However, previous studies have sugg
PMID 24726872

GABARBP down-regulates HIF-1α expression through the VEGFR-2 and PI3K/mTOR/4E-BP1 pathways.

Park SH1, Kim BR2, Lee JH3, Park ST1, Lee SH4, Dong SM2, Rho SB5.
Cellular signalling.Cell Signal.2014 Jul;26(7):1506-13. doi: 10.1016/j.cellsig.2014.03.017. Epub 2014 Mar 29.
Human γ-aminobutyrate type A (GABAA) receptor-binding protein (GABARBP), a tumor suppressor protein with apoptotic function, can be inhibited in response to angiogenesis through the PI3K/Akt signaling cascades. Here, we investigated whether GABARBP over-expression could regulate vascular endothelia
PMID 24686084

Japanese Journal

Yokukansan Enhances Pentobarbital-Induced Sleep in Socially Isolated Mice: Possible Involvement of GABAA – Benzodiazepine Receptor Complex

Egashira Nobuaki,Nogami Ai,Iwasaki Katsunori,Ishibashi Ayumi,Uchida Naoki,Takasaki Kotaro,Mishima Kenichi,Nishimura Ryoji,Oishi Ryozo,Fujiwara Michihiro
Journal of Pharmacological Sciences 116(3), 316-320, 2011
… These findings suggest that the GABAA – … benzodiazepine receptor complex, but not 5-HT1A receptors, is involved in the reversal effect of YKS on the decrease of pentobarbital sleep by social isolation. …
NAID 130001014462

Effect of Heat Exposure on Aminophylline-Induced Convulsions in Mice

Ochi Rika,Suemaru Katsuya,Watanabe Shinichi,Yamaguchi Takumi,Takechi Kenshi,Kawasaki Hiromu,Araki Hiroaki
Biological & Pharmaceutical Bulletin 34(5), 666-670, 2011
… The shortened time for onset of convulsions was blocked by the NMDA receptor antagonist dizocilpine (0.1, 0.3 mg/kg, i.p.). … However, the GABAA receptor agonist muscimol (1, 2 mg/kg, i.p.) did not have any effect. … However, the pro-convulsant actions of picrotoxin (3—4 mg/kg, i.p.), a GABAA receptor antagonist, were not affected by increased temperatures. …
NAID 130000657777