GABAA receptor

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. Upon activation, the GABAA 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 active site of the GABAA 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]

Mild inhibition of neuronal firing by drugs acting at the GABAA receptor causes a reduction of anxiety in the patient (an anxiolytic effect) while more pronounced inhibition induces sleep (sedation) and in extreme cases of overdose, may result in death.

Contents

Target for benzodiazepines

The ionotropic GABAA receptor protein complex is also the molecular target of the benzodiazepine (BZ) 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 GABAA receptors (see figure to the right).[6][7] 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,[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 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".[9]

In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where 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 sedatory and anxiolytic effects.

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.[10] 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,[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 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

The receptor is a multimeric 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 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 is typically inhibitory, reducing the activity of the neuron. The GABAA 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

GABAA 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 GABAA receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.[16]

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

There are three ρ units (GABRR1, GABRR2, GABRR3), however these do not coassemble with the classical GABAA units listed above,[18] but rather homooligomerize to form GABAA-ρ receptors (formerly designated as GABAC receptors).

Five subunits can combine in different ways to form GABAA channels. The minimal requirement to produce a GABA-gated ion channel is the inclusion of both α and β subunits,[19] 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,[20] 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 GABAA receptor complex and modulate it besides GABA itself.

Types

Examples

Effects

Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. Some such as muscimol 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.[24]

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 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.[25] 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:

Distribution

As GABAA 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, 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 and GABAA receptors can influence cell proliferation.[27]

See also

References

  1. ^ Clayton T, Chen JL, Ernst M, Richter L, Cromer BA, Morton CJ, Ng H, Kaczorowski CC, Helmstetter FJ, Furtmüller R, Ecker G, Parker MW, Sieghart W, Cook JM (2007). "An updated unified pharmacophore model of the benzodiazepine binding site on gamma-aminobutyric acid(a) receptors: correlation with comparative models". Curr. Med. Chem. 14 (26): 2755–75. doi:10.2174/092986707782360097. PMID 18045122. 
  2. ^ Campagna-Slater V, Weaver DF (January 2007). "Molecular modelling of the GABAA ion channel protein". J. Mol. Graph. Model. 25 (5): 721–30. doi:10.1016/j.jmgm.2006.06.001. PMID 16877018. 
  3. ^ Sancar F, Ericksen SS, Kucken AM, Teissére JA, Czajkowski C (January 2007). "Structural Determinants for High-Affinity Zolpidem Binding to GABA-A receptors". Mol. Pharmacol. 71 (1): 38–46. doi:10.1124/mol.106.029595. PMC 2583146. PMID 17012619. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2583146. 
  4. ^ Santhakumar V, Wallner M, Otis TS (May 2007). "Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition". Alcohol 41 (3): 211–21. doi:10.1016/j.alcohol.2007.04.011. PMC 2040048. PMID 17591544. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2040048. 
  5. ^ Johnston GAR (1996). "GABAA Receptor Pharmacology". Pharmacology and Therapeutics 69 (3): 173–198. doi:10.1016/0163-7258(95)02043-8. PMID 8783370. 
  6. ^ Sigel E (August 2002). "Mapping of the benzodiazepine recognition site on GABAA receptors". Curr Top Med Chem 2 (8): 833–9. doi:10.2174/1568026023393444. PMID 12171574. 
  7. ^ Akabas MH (2004). "GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures". Int. Rev. Neurobiol.. International Review of Neurobiology 62: 1–43. doi:10.1016/S0074-7742(04)62001-0. ISBN 978-0-12-366862-2. PMID 15530567. 
  8. ^ 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". J. Neurochem. 88 (6): 1431–8. doi:10.1046/j.1471-4159.2003.02264.x. PMID 15009644. 
  9. ^ Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (1 June 1998). "International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function". Pharmacol. Rev. 50 (2): 291–313. PMID 9647870. http://pharmrev.aspetjournals.org/cgi/content/abstract/50/2/291. 
  10. ^ Atack, JR (2003). "Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site". Current drug targets. CNS and neurological disorders 2 (4): 213–32. doi:10.2174/1568007033482841. PMID 12871032. 
  11. ^ Hanson SM, Czajkowski C (March 2008). "Structural mechanisms underlying benzodiazepine modulation of the GABAA receptor". J. Neurosci. 28 (13): 3490–9. doi:10.1523/JNEUROSCI.5727-07.2008. PMC 2410040. PMID 18367615. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2410040. 
  12. ^ Twyman RE, Rogers CJ, Macdonald RL (March 1989). "Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital". Ann. Neurol. 25 (3): 213–20. doi:10.1002/ana.410250302. PMID 2471436. 
  13. ^ 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". J. Neurosci. 23 (33): 10650–61. PMID 14627650. 
  14. ^ 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. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181. 
  15. ^ Chen K, Li HZ, Ye N, Zhang J, Wang JJ (2005). "Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro". Brain Res Bull 67 (4): 310–8. doi:10.1016/j.brainresbull.2005.07.004. PMID 16182939. 
  16. ^ Cossart R, Bernard C, Ben-Ari Y (2005). "Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies". Trends Neurosci 28 (2): 108–15. doi:10.1016/j.tins.2004.11.011. PMID 15667934. 
  17. ^ a b c Martin IL and Dunn SMJ. GABA receptors A review of GABA and the receptors to which it binds. Tocris Cookson LTD.
  18. ^ Enz R, Cutting GR (1998). "Molecular composition of GABAC receptors". Vision Res 38 (10): 1431–41. doi:10.1016/S0042-6989(97)00277-0. PMID 9667009. 
  19. ^ Connolly CN, Krishek BJ, McDonald B, Smart TG, Moss SJ (1996). "Assembly and cell surface expression of heteromeric and homomeric g-aminobutyric acid type A receptors". J Biol Chem 271 (1): 89–96. doi:10.1074/jbc.271.1.89. PMID 8550630. 
  20. ^ Colquhoun D, Sivilotti LG (2004). "Function and structure in glycine receptors and some of their relatives". Trends Neurosci 27 (6): 337–44. doi:10.1016/j.tins.2004.04.010. PMID 15165738. 
  21. ^ Hunter, A (2006). "Kava (Piper methysticum) back in circulation". Australian Centre for Complementary Medicine 25 (7): 529. 
  22. ^ (a) Herd MB, Belelli D, Lambert JJ (2007). "Neurosteroid modulation of synaptic and extrasynaptic GABAA 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 GABAA 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1600006. ; (d) Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (2005). "Neurosteroid access to the GABAA 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 GABAA 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 GABAA 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. 
  23. ^ 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: 362–9. PMID 12640458. 
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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 GABAA receptors". Bioorg. Med. Chem. 16 (14): 6936–48. doi:10.1016/j.bmc.2008.05.049. PMID 18541432. 
  27. ^ ten Hoeve AL (2012). GABA receptors and the immune system. Thesis, Utrecht University

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