Abstract
The γ-aminobutyric acid type A receptor (GABA (A) receptor) is a membrane protein activated by the neurotransmitter GABA. Structurally, this major inhibitory neurotransmitter receptor in the human central nervous system is a pentamer that can be built from a selection of 19 subunits consisting of α(1,2,3,4,5 or 6), β (1,2 or 3), γ (1,2 or 3), ρ (1,2 or 3), and δ, π, θ, and ε. This creates several possible pentameric arrangements, which also influence the pharmacological and physiological properties of the receptor. The complexity and heterogeneity of the receptors are further increased by the addition of short and long splice variants in several subunits and the existence of multiple allosteric binding sites and expansive ligands that can bind to the receptors. Therefore, a comprehensive understanding of the structure and function of the receptors is required to gain novel insights into the consequences of receptor dysfunction and subsequent drug development studies. Notably, advancements in computational-aided studies have facilitated the elucidation of residual interactions and exploring energy binding, which may otherwise be challenging to investigate. In this review, we aim to summarize the current understanding of the structure and function of GABA (A) receptors obtained from advancements in computational-aided applications.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Data sharing is not applicable to this article as no new data were created or analysed in this review work.
Code Availability
Not applicable.
References
Alvarez LD, Pecci A (2018) Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor. J Steroid Biochem Mol Biol 182(March):72–80. https://doi.org/10.1016/j.jsbmb.2018.04.012
Amundarain MJ, Ribeiro RP, Costabel MD, Giorgetti A (2019a) GABA A receptor family: overview on structural characterization. Future Med Chem 11(3):229–246. https://doi.org/10.4155/fmc-2018-0336
Amundarain MJ, Viso JF, Zamarreño F, Giorgetti A, Costabel M (2019b) Orthosteric and benzodiazepine cavities of the α1β2γ2 GABA A receptor: insights from experimentally validated in silico methods. J Biomol Struct Dynamics 37(6):1597–1615. https://doi.org/10.1080/07391102.2018.1462733
Ashby JA, McGonigle IV, Price KL, Cohen N, Comitani F, Dougherty DA, Molteni C, Lummis SCR (2012) GABA binding to an insect GABA receptor: a Molecular Dynamics and Mutagenesis Study. Biophys J 103(10):2071–2081. https://doi.org/10.1016/j.bpj.2012.10.016
Barrera NP, Edwardson JM (2008) The subunit arrangement and assembly of ionotropic receptors. Trends Neurosci 31(11):569–576. https://doi.org/10.1016/j.tins.2008.08.001
Baumann SW, Baur R, Sigel E (2002) Forced Subunit Assembly in α1β2γ2 GABA A receptors. J Biol Chem 277(48):46020–46025. https://doi.org/10.1074/jbc.m207663200
Baumann SW, Baur R, Sigel E (2003) Individual properties of the two functional agonist sites in GABA(A) receptors. J Neurosci 23(35):11158–11166. https://doi.org/10.1523/JNEUROSCI.23-35-11158.200
Berezhnoy D, Nyfeler Y, Gonthier A, Schwob H, Goeldner M, Sigel E (2004) On the benzodiazepine binding Pocket in GABAA receptors. J Biol Chem 279(5):3160–3168. https://doi.org/10.1074/jbc.M311371200
Berezhnoy D, Gibbs TT, Farb DH (2009) Docking of 1, 4-Benzodiazepines in the α1/γ2 GABA(A) receptor modulator site. Mol Pharmacol 76:440–450. https://doi.org/10.1124/mol.109.054650
Bergmann R, Kongsbak K, Sørensen PL, Sander T, Balle T (2013) A unified model of the GABA a receptor comprising agonist and benzodiazepine binding Sites. PLoS ONE 8(1). https://doi.org/10.1371/journal.pone.0052323
Bollan KA, Baur R, Hales TG, Sigel E, Connolly CN (2008) The promiscuous role of the epsilon subunit in GABA (A) receptor biogenesis. Mol Cell Neurosci 37(3):610–621. https://doi.org/10.1016/j.mcn.2007.12.011
Bormann J (2000) The ABC of GABA receptors. Trends Pharmacol Sci 21(1):16–19. https://doi.org/10.1016/S0165-6147(99)01413-3
Bowery NG, Smart TG (2006) GABA and glycine as neurotransmitters: A brief history. British Journal of Pharmacology, 147(SUPPL. 1), 109–119. https://doi.org/10.1038/sj.bjp.0706443
Brejc K, Van Dijk WJ, Klaassen RV, Schuurmans M, Van Der Oost J, Smit AB, Sixma TK (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411(6835):269–276. https://doi.org/10.1038/35077011
Brodzki M, Rutkowski R, Jatczak M, Kisiel M, Czyzewska MM, Mozrzymas JW (2016) Comparison of kinetic and pharmacological profiles of recombinant α1γ2L and α1β2γ2L GABA A receptors - A clue to the role of intersubunit interactions. Eur J Pharmacol 784:81–89. https://doi.org/10.1016/j.ejphar.2016.05.015
Buhr A, Sigel E (1997) A point mutation in the gamma2 subunit of gamma-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity. Proc Natl Acad Sci USA 94(16):8824–8829. https://doi.org/10.1073/pnas.94.16.8824
Carpenter TS, Lightstone FC (2016) An Electrostatic Funnel in the GABA-Binding pathway. PLoS Comput Biol 12(4):1–23. https://doi.org/10.1371/journal.pcbi.1004831
Chang Y, Wu W, Zhang J, Huang Y (2009) Allosteric activation mechanism of the cys-loop receptors. Acta Pharmacol Sin 30(6):663–672. https://doi.org/10.1038/aps.2009.51
Che Has AT, Absalom N, Van Nieuwenhuijzen PS, Clarkson AN, Ahring PK, Chebib M (2016) Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABA A receptors: evidence of a novel benzodiazepine site in the α1-α1 interface. Sci Rep 6(March):1–12. https://doi.org/10.1038/srep28674
Chebib M, Johnston GAR (1999) The ABC of GABA receptors: a brief review. Clin Exp Pharmacol Physiol 26(11):937–940. https://doi.org/10.1046/j.1440-1681.1999.03151.x
Clayton T, Poe MM, Rallapalli S, Biawat P, Savić MM, Rowlett JK et al (2015) A review of the updated pharmacophore for the alpha 5 GABA(A) benzodiazepine receptor model. Int J Med Chem 1–54. https://doi.org/10.1155/2015/430248
Crnjar A, Comitani F, Melis C, Molteni C (2019) Mutagenesis computer experiments in pentameric ligand-gated ion channels: the role of simulation tools with different resolution. Interface Focus 9(3). https://doi.org/10.1098/rsfs.2018.0067
Crnjar A, Mesoy SM, Lummis SCR, Molteni C (2021) A single mutation in the outer lipid-facing Helix of a Pentameric Ligand-Gated Ion Channel affects Channel function through a radially-propagating mechanism. Front Mol Biosci 8(April):1–15. https://doi.org/10.3389/fmolb.2021.644720
Darlison MG, Pahal I, Thode C (2005) Consequences of the evolution of the GABAA receptor gene family. Cell Mol Neurobiol 25(3–4):607–624. https://doi.org/10.1007/s10571-005-4004-4
Davies PA, Hanna MC, Hales TG, Kirkness EF (1997) Insensitivity to anaesthetic agents conferred by a class of GABA (A) receptor subunit. Nature 385(6619):820–823. https://doi.org/10.1038/385820a0
Elgarf AA, Siebert DCB, Steudle F, Draxler A, Li G, Huang S, Cook JM, Ernst M, Scholze P (2018) Different benzodiazepines bind with distinct binding modes to GABA A receptors. ACS Chem Biol 13(8):2033–2039. https://doi.org/10.1021/acschembio.8b00144
Ernst M, Sieghart W (2015) GABA A receptor subtypes: structural variety raises hope for new therapy concepts. e-Neuroforum 6:97–103. https://doi.org/10.1007/s13295-015-0016-9
Ernst M, Brauchart D, Boresch S, Sieghart W (2003) Comparative modeling of GABAA receptors: limits, insights, future developments. Neuroscience 119(4):933–943. https://doi.org/10.1016/S0306-4522(03)00288-4
Ernst M, Bruckner S, Boresch S, Sieghart W (2005) Comparative models of GABA. Mol Pharmacol 68(5):1291–1300. https://doi.org/10.1124/mol.105.015982.ture
Estrada-Mondragon A, Lynch JW (2015) Functional characterization of ivermectin binding sites in α1β2γ2L GABA(A) receptors. Front Mol Neurosci 8(September):1–13. https://doi.org/10.3389/fnmol.2015.00055
Fabjan J, Koniuszewski F, Schaar B, Ernst M (2021) Structure-Guided Computational Methods Predict Multiple Distinct Binding Modes for Pyrazoloquinolinones in GABAA Receptors. Frontiers in Neuroscience, 14. https://doi.org/10.3389/fnins.2020.611953
Garcia P, Kolesky S, Jenkins A (2010) General anesthetic actions on GABAA receptors. Curr Neuropharmacol 8(1):2–9. https://doi.org/10.2174/157015910790909502
Gharpure A, Teng J, Zhuang Y, Noviello CM, Walsh RM Jr., Cabuco R et al (2019) Agonist selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic receptor. Neuron 104(3):501–511. https://doi.org/10.1016/j.neuron.2019.07.030
Gielen M, Barilone N, Corringer P-J (2020) The desensitization pathway of GABA (A) receptors, one subunit at a time. Nat Commun 11:1–14. https://doi.org/10.1038/s41467-020-19218-6
Goossens K, De Winter H (2018) Molecular Dynamics Simulations of membrane proteins: an overview [Review-article]. J Chem Inf Model 58(11):2193–2202. https://doi.org/10.1021/acs.jcim.8b00639
Griffin CE, Kaye AM, Bueno FR, Kaye AD (2013) Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J 13(2):214–223
Hanson SM, Czajkowski C (2008) Structural mechanisms underlying benzodiazepine modulation of the GABAA receptor. J Neurosci 28(13):3490–3499. https://doi.org/10.1523/jneurosci.5727-07.2008
Hanson SM, Morlock EV, Satyshur KA, Czajkowski C (2008) Structural requirements for eszopiclone and zolpidem binding to the GABA A receptor are different. J Med Chem 27(51):7243–7252. https://doi.org/10.1021/jm800889m
Hénin J, Salari R, Murlidaran S, Brannigan G (2014) A predicted binding site for cholesterol on the GABAA receptor. Biophys J 106(9):1938–1949. https://doi.org/10.1016/j.bpj.2014.03.024
Iorio MT, Vogel FD, Koniuszewski F, Scholze P, Rehman S, Simeone X, Schnürch M, Mihovilovic MD, Ernst M (2020) GABA(A) receptor ligands often interact with binding Sites in the transmembrane domain and in the Extracellular Domain — can the Promiscuity Code be cracked ? Int J Mol Sci 21(334). https://doi.org/10.3390/ijms21010334
Johnston GAR (1994) GABA (A) Receptors - as complex as ABC? Clinical and Experimental Pharmacology and Physiology, 21(7), 521–526. https://doi.org/10.1111/j.1440-1681.1994.tb02550.x
Johnston GAR (2013) Advantages of an antagonist: bicuculline and other GABA antagonists. Br J Pharmacol 169:328–336. https://doi.org/10.1111/bph.12127
Kasaragod VB, Mortensen M, Hardwick SW, Wahid AA, Dorovykh V, Chirgadze DY, Smart TG, Miller PS (2022) Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors. Nature 602(7897):529–533. https://doi.org/10.1038/s41586-022-04402-z
Khatri A, Sedelnikova A, Weiss DS (2009) Structural rearrangements in loop F of the GABA receptor signal ligand binding, not channel activation. Biophys J 96(1):45–55. https://doi.org/10.1016/j.bpj.2008.09.011
Khayenko V, Maric HM (2019) Targeting GABA(A)R-Associated Proteins: New Modulators, Labels and Concepts. Front Mol Neurosci 12(June):1–10. https://doi.org/10.3389/fnmol.2019.00162
Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM Jr, Lindahl RMW, E., Hibbs RE (2020) Shared structural mechanisms of general anaesthetics and benzodiazepines. Nature, December 2019. https://doi.org/10.1038/s41586-020-2654-5
Koniuszewski F, Vogel FD, Bampali K, Fabjan J, Seidel T, Scholze P et al (2022) Molecular Mingling: multimodal predictions of ligand promiscuity in Pentameric Ligand-Gated Ion channels. Front Mol Biosci 9. https://doi.org/10.3389/fmolb.2022.860246
Lagrange AH, Hu NN, Macdonald RL (2018) GABA beyond the synapse: defining the subtype-specific pharmacodynamics of non-synaptic GABAA receptors. J Physiol 596(18):4475–4495. https://doi.org/10.1113/JP276187
Laverty D, Desai R, Uchański T, Masiulis S, Stec WJ, Malinauskas T, Zivanov J, Pardon E, Steyaert J, Miller KW, Aricescu AR (2019) Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer. Nature 565(7740):516–520. https://doi.org/10.1038/s41586-018-0833-4
Law RJ, Lightstone FC (2009) Modeling neuronal nicotinic and GABA receptors: important interface salt-links and protein dynamics. Biophys J 97(6):1586–1594. https://doi.org/10.1016/j.bpj.2009.06.044
Law RJ, Henchman RH, Mccammon JA (2005) A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor. PNAS 102(19):6813–6818. https://doi.org/10.1073/pnas.0407739102
Liu S, Xu L, Guan F, Liu YT, Cui Y, Zhang Q, Zheng X, Bi GQ, Zhou ZH, Zhang X, Ye S (2018) Cryo-EM structure of the human α5β3 GABA A receptor. Cell Res 28(9):958–961. https://doi.org/10.1038/s41422-018-0077-8
Luscher B, Fuchs T, Kilpatrick CL (2011) GABA (A) receptor trafficking-mediated plasticity of Inhibitory Synapses. Neuron 70(3):385–409. https://doi.org/10.1016/j.neuron.2011.03.024.GABA
Lynagh T, Pless SA (2014) Principles of agonist recognition in Cys-loop receptors. Frontiers in Physiology, 5 APR(April), 1–12. https://doi.org/10.3389/fphys.2014.00160
Maldifassi MC, Baur R, Sigel E (2016) Molecular mode of action of CGS 9895 at alpha1 beta2 gamma2 GABAA receptors. J Neurochem 138:722–730. https://doi.org/10.1111/jnc.13711
Masiulis S, Desai R, Uchański T, Martin S, Laverty I, Karia D, Malinauskas D, Zivanov T, Pardon J, Kotecha E, Steyaert A, Miller J, K. W., Aricescu AR (2019) GABA A receptor signalling mechanisms revealed by structural pharmacology. Nature 565(7740):454–459. https://doi.org/10.1038/s41586-018-0832-5
McGrath M, Hoyt H, Pence A, Forman SA, Raines DE (2021) Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABAA receptor: in vitro and in vivo studies. Br J Pharmacol 178(24):4842–4858. https://doi.org/10.1111/bph.15662
Mercado J, Czajkowski C (2006) Charged residues in the α1 and β2 Pre-M1 regions involved in GABA A receptor activation. J Neurosci 26(7):2031–2040. https://doi.org/10.1523/JNEUROSCI.4555-05.2006
Miller PS, Aricescu AR (2014) Crystal structure of a human GABAA receptor. Nature 512(7514):270–275. https://doi.org/10.1038/nature13293
Mohamad FH, Has ATC (2019) The α5-Containing GABA (A) receptors - a brief Summary. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1246-4
Mortensen M, Smart TG (2006) Extrasynaptic αβ subunit GABAA receptors on rat hippocampal pyramidal neurons. J Physiol 577(3):841–856. https://doi.org/10.1113/jphysiol.2006.117952
Murlidaran S, Hénin J, Brannigan G (2019) Competitive dewetting underlies site-specific binding of general anesthetics to GABA(A) receptors. https://doi.org/10.1101/694612
Naffaa MM, Hung S, Chebib M, Johnston GAR, Hanrahan JR (2017) GABA-ρ receptors: distinctive functions and molecular pharmacology. Br J Pharmacol 174(13):1881–1894. https://doi.org/10.1111/bph.13768
Newell JG, Czajkowski C (2003) The GABAA receptor α1 subunit Pro174-Asp191 segment is involved in GABA binding and channel gating. J Biol Chem 278(15):13166–13172. https://doi.org/10.1074/jbc.M211905200
O’Toole KK, Jenkins A (2011) Discrete M3-M4 intracellular loop subdomains control specific aspects of γ-aminobutyric acid type A receptor function. J Biol Chem 286(44):37990–37999. https://doi.org/10.1074/jbc.M111.258012
Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of -aminobutyric AcidA receptors: classification on the basis of Subunit Composition, Pharmacology, and function. Update. Pharmacol Rev 60(3):243–260. https://doi.org/10.1124/pr.108.00505
Olsen RW, Hanchar HJ, Meera P, Wallner M (2007) GABAA receptor subtypes: the one glass of wine receptors. Alcohol 41(3):201–209. https://doi.org/10.1016/j.alcohol.2007.04.006
Pantsar T, Poso A (2018) Binding Affinity via Docking: Fact and Fiction. Molecules 23:1–11. https://doi.org/10.3390/molecules23081899
Payghan PV, Bera I, Bhattacharyya D, Ghoshal N (2016) Capturing state-dependent dynamic events of GABAA-receptors: a microscopic look into the structural and functional insights. J Biomol Struct Dynamics 34(8):1818–1837. https://doi.org/10.1080/07391102.2015.1094410
Payghan PV, Bera I, Bhattacharyya D, Ghoshal N (2018) Computational studies for structure-based drug Designing Against Transmembrane Receptors: pLGICs and class A GPCRs. Front Phys 6(September):1–23. https://doi.org/10.3389/fphy.2018.00052
Payghan PV, Roy N, Bhattacharyya S, D., Ghoshal N (2019) Cross-talk between allosteric and orthosteric binding sites of γ-amino butyric acid type A receptors (GABAA-Rs): a computational study revealing the structural basis of selectivity. J Biomol Struct Dynamics 37(12):3065–3080. https://doi.org/10.1080/07391102.2018.1508367
Phulera S, Zhu H, Yu J, Claxton DP, Yoder N, Yoshioka C, Gouaux E (2018) Cryo-EM structure of the benzodiazepine- sensitive a1b1g2S tri-heteromeric GABAA receptor in complex with GABA. ELIFE 1(i):1–21. https://doi.org/10.7554/eLife.39383
Polovinkin L, Hassaine G, Perot J, Neumann E, Jensen AA, Lefebvre SN et al (2018) Conformational transitions of the serotonin 5-HT3 receptor. Nature 563(7730):275–279. https://doi.org/10.1038/s41586-018-0672-3
Puthenkalam R, Hieckel M, Simeone X, Suwattanasophon C, Feldbauer RV, Ecker GF, Ernst M (2016) Structural studies of GABAA receptor binding Sites: which experimental structure tells us what? Front Mol Neurosci 9(June):1–20. https://doi.org/10.3389/fnmol.2016.00044
Qian H, Pan Y (2002) Co-assembly of GABA ρ subunits with the GABAA receptor β2 subunit cloned from white perch retina. Mol Brain Res 103:62–70. https://doi.org/10.1016/s0169-328x(02)00140-7
Ralvenius WT, Benke D, Acuña MA, Rudolph U, Zeilhofer HU (2015) Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype. Nat Commun 6. https://doi.org/10.1038/ncomms7803
Ramerstorfer J, Furtmüller R, Sarto-jackson I, Varagic Z, Sieghart W, Ernst M (2011) The GABA (A) receptor α + β – interface: a Novel Target for Subtype selective drugs. J Neurosci 31(3):870–877. https://doi.org/10.1523/JNEUROSCI.5012-10.2011
Richter L, De Graaf C, Sieghart W, Varagic Z, Mörzinger M, De Esch IJP, Ecker GF, Ernst M (2012) Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands. Nat Chem Biol 8(5):455–464. https://doi.org/10.1038/nchembio.917
Salari R, Murlidaran S, Brannigan G (2014) Pentameric ligand-gated ion channels: insights from computation. Mol Simul 40(10–11):821–829. https://doi.org/10.1080/08927022.2014.896462
Sander T, Frølund B, Bruun AT, Ivanov I, Andrew J, Balle T (2011) New insights into the GABA (A) receptor structure and orthosteric ligand binding: receptor modelling guided by experimental data. Proteins 79(5):1458–1477. https://doi.org/10.1002/prot.22975
Sente A, Desai R, Naydenova K, Malinauskas T, Jounaidi Y, Miehling J, Zhou X, Masiulis S, Hardwick SW, Chirgadze DY, Miller KW, Aricescu AR (2022) Differential assembly diversifies GABA (A) receptor structures and signalling. Nature 604:190–194. https://doi.org/10.1038/s41586-022-04517-3
Sieghart W (2014) Allosteric modulation of GABA A receptors via multiple drug-binding Sites. Diversity and functions of GABA receptors: a tribute to Hanns Möhler, Part A, 1st edn. Elsevier Inc. https://doi.org/10.1016/bs.apha.2014.10.002
Sieghart W, Sperk G (2002) Subunit composition, distribution and function of GABA. Curr Top Med Chem 795–816. https://doi.org/10.2174/1568026023393507
Sigel E (2002) Mapping of the Benzodiazepine Recognition Site on GABA-A receptors. Curr Top Med Chem 2(8):833–839. https://doi.org/10.2174/1568026023393444
Sigel E, Steinmann ME (2012) Structure, function, and modulation of GABAA receptors. J Biol Chem 287(48):40224–40231. https://doi.org/10.1074/jbc.R112.386664
Sigel E, Baur R, Boulineau N, Minier F (2006) Impact of subunit positioning on GABA A receptor function. Biochem Soc Trans 34(5):868–871. https://doi.org/10.1042/bst0340868
Sinkkonen ST, Hanna MC, Kirkness EF, Korpi ER (2000) GABA a receptor ε and θ subunits display unusual structural variation between species and are enriched in the rat locus Ceruleus. J Neurosci 20(10):3588–3595. https://doi.org/10.1523/JNEUROSCI.20-10-03588.2000
Smart TG, Stephenson FA (2019) A half century of γ-aminobutyric acid. Brain and Neuroscience Advances 3:239821281985824. https://doi.org/10.1177/2398212819858249
Sommer B (2013) Membrane packing problems: a short review on computational membrane modeling methods and tools. Comput Struct Biotechnol J 5(6):e201302014. https://doi.org/10.5936/csbj.201302014
Tan KR, Baur R, Gonthier A, Goeldner M, Sigel E (2007) Two neighboring residues of loop A of the α1 subunit point towards the benzodiazepine binding site of GABAA receptors. FEBS Lett 581(24):4718–4722. https://doi.org/10.1016/j.febslet.2007.08.068
Teissére JA, Czajkowski C (2001) A (beta)-strand in the (gamma)2 subunit lines the benzodiazepine binding site of the GABA A receptor: structural rearrangements detected during channel gating. J Neurosci 21(14):4977–4986. https://doi.org/10.1523/JNEUROSCI.21-14-04977.2001
Terejko K, Kaczor PT, Michałowski MA, Dąbrowska A, Mozrzymas JW (2020) The C loop at the orthosteric binding site is critically involved in GABAA receptor gating. Neuropharmacology, 166(April 2019). https://doi.org/10.1016/j.neuropharm.2019.107903
Thompson AJ, Lester HA, Lummis SCR (2010) The structural basis of function in Cys-loop receptors. In Quarterly Reviews of Biophysics (Vol. 43, Issue 4, pp. 449–499). https://doi.org/10.1017/S0033583510000168
Varagic Z, Wimmer L, Schnurch M, Mihovilovic MD, Huang S, Rallapalli S et al (2013) Identification of novel positive allosteric modulators and null modulators at the GABAA receptor alpha + beta- interface. Br J Pharmacol 169:371–383. https://doi.org/10.1111/bph.12151
Várnai C, Irwin BWJ, Payne MC, Csányi G, Chau PL (2020) Functional movements of the GABA type A receptor. Phys Chem Chem Phys 22(28):16023–16031. https://doi.org/10.1039/d0cp01128b
Vijayan RSK, Bhattacharyya D, Ghoshal N (2012) Deciphering the binding mode of Zolpidem to GABA A α1 receptor - insights from molecular dynamics simulation. J Mol Model 18(4):1345–1354. https://doi.org/10.1007/s00894-011-1142-0
Walters RJ, Hadley SH, Morris KD, Amin J (2000) Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms. Nat Neurosci 3(12):1274–1281. https://doi.org/10.1038/81800
Weir CJ (2016) Ion channels, receptors, agonists and antagonists. Anaesth Intensive Care Med 17(12):645–651. https://doi.org/10.1016/j.mpaic.2016.09.016
Wilke K, Gaul R, Klauck SM, Poustka A (1997) A gene in human chromosome Band Xq28 (GABRE) defines a putative New Subunit Class of the GABA a neurotransmitter receptor. Genomics 10(45):1–10. https://doi.org/10.1006/geno.1997.4885
Woll KA, Murlidaran S, Pinch BJ, Hénin J, Wang X, Salari R, Covarrubias M, Dailey WP, Brannigan G, Garcia BA, Eckenhoff RG (2016) A novel bifunctional alkylphenol anesthetic allows characterization of γ-aminobutyric acid, type A (GABAA), receptor subunit binding selectivity in synaptosomes. J Biol Chem 291(39):20473–20486. https://doi.org/10.1074/jbc.M116.736975
Xie HB, Sha Y, Wang J, Cheng MS (2013a) Some insights into the binding mechanism of the GABAA receptor: a combined docking and MM-GBSA study. J Mol Model 19(12):5489–5500. https://doi.org/10.1007/s00894-013-2049-8
Xie HB, Wang J, Sha Y, Cheng MS (2013b) Molecular dynamics investigation of Cl- transport through the closed and open states of the 2α12β2γ 2 GABAA receptor. Biophys Chem 180–181:1–9. https://doi.org/10.1016/j.bpc.2013.05.004
Zheleznova NN, Sedelnikova A, Weiss DS (2009) Function and modulation of δ-containing GABA (A) receptors. Psychoneuroendocrinology, 34 Suppl 1, S67-73. https://doi.org/S0306-4530(09)00254-6 https://doi.org/10.1016/j.psyneuen.2009.08.010 [pii]
Zhu S, Noviello CM, Teng J, Walsh RM, Kim JJ, Hibbs RE (2018) Structure of a human synaptic GABA A receptor. Nature 559(7712):67–88. https://doi.org/10.1038/s41586-018-0255-3
Zhu S, Sridhar A, Teng J, Howard RJ, Lindahl E, Hibbs RE (2022) Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities. Nat Commun 13:4582. https://doi.org/10.1038/s41467-022-32212-4
Author information
Authors and Affiliations
Contributions
F.H.M: Designing and drafting the manuscript. M.A.M.J: Preparing the figures and revising the manuscript. A.T.C.H: Drafting and revising the manuscript critically and approving the manuscript to be published.
Corresponding author
Ethics declarations
Conflicts of interest/Competing Interests
The authors state no conflict of interest exists.
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for publication
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mohamad, F.H., Mohamad Jamali, M. & Che Has, A. Structure-function Studies of GABA (A) Receptors and Related computer-aided Studies. J Mol Neurosci 73, 804–817 (2023). https://doi.org/10.1007/s12031-023-02158-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-023-02158-3