Hostname: page-component-5b777bbd6c-gtgcz Total loading time: 0 Render date: 2025-06-20T09:02:57.534Z Has data issue: false hasContentIssue false
  • English
  • Français

Molecular mechanisms of the GABA type A receptor function

Published online by Cambridge University Press:  14 January 2025

Michał A. Michałowski Open the ORCID record for Michał A. Michałowski [Opens in a new window] ,
Karol Kłopotowski ,
Grzegorz Wiera ,
Marta M. Czyżewska  and
Jerzy W. Mozrzymas
Michał A. Michałowski*
Affiliation:
Faculty of Medicine, Department of Biophysics and Neuroscience, Wroclaw Medical University, Wrocław, Poland
Karol Kłopotowski
Affiliation:
Faculty of Medicine, Department of Biophysics and Neuroscience, Wroclaw Medical University, Wrocław, Poland
Grzegorz Wiera
Affiliation:
Faculty of Medicine, Department of Biophysics and Neuroscience, Wroclaw Medical University, Wrocław, Poland
Marta M. Czyżewska
Affiliation:
Faculty of Medicine, Department of Biophysics and Neuroscience, Wroclaw Medical University, Wrocław, Poland
Jerzy W. Mozrzymas
Affiliation:
Faculty of Medicine, Department of Biophysics and Neuroscience, Wroclaw Medical University, Wrocław, Poland
*
Corresponding author: Michał A. Michałowski; Email: michal.michalowski@umw.edu.pl
Get access Rights & Permissions [Opens in a new window]

Abstract

The GABA type A receptor (GABAAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia. GABAAR is also a target for multiple physiologically and clinically relevant modulators, such as benzodiazepines (BDZs), general anesthetics, and neurosteroids. The first GABAAR structure appeared in 2014, but the past years have brought a particularly abundant surge in structural data for these receptors with various ligands and modulators. Although the open conformation remains elusive, this novel information has pushed the structure–function studies to an unprecedented level. Electrophysiology, mutagenesis, photolabeling, and in silico simulations, guided by novel structural information, shed new light on the molecular mechanisms of receptor functioning. The main goal of this review is to present the current knowledge of GABAAR functional and structural properties. The review begins with an outline of the functional and structural studies of GABAAR, accompanied by some methodological considerations, especially biophysical methods, enabling the reader to follow how major breakthroughs in characterizing GABAAR features have been achieved. The main section provides a comprehensive analysis of the functional significance of specific structural elements in GABAARs. We additionally summarize the current knowledge on the binding sites for major GABAAR modulators, referring to the molecular underpinnings of their action. The final chapter of the review moves beyond examining GABAAR as an isolated macromolecule and describes the interactions of the receptor with other proteins in a broader context of inhibitory plasticity. In the final section, we propose a general conclusion that agonist binding to the orthosteric binding sites appears to rely on local interactions, whereas conformational transitions of bound macromolecule (gating) and allosteric modulation seem to reflect more global phenomena involving vast portions of the macromolecule.

Keywords

Structural biologyElectrophysiologyBioinformaticsProtein structure & functionNeuro-biophysics
Type
Review
Information
Quarterly Reviews of Biophysics , Volume 58 , 2025 , e3
Copyright
© The Author(s), 2025. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Akk, G, Bracamontes, J, and Steinbach, JH (2001) Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the α subunit. Journal of Physiology 532(3), 673–684. https://doi.org/10.1111/J.1469-7793.2001.0673E.X.CrossRefGoogle ScholarPubMed
Akk, G, Germann, AL, Sugasawa, Y, Pierce, SR, Evers, AS, and Steinbach, JH (2020) Enhancement of muscimol binding and gating by allosteric modulators of the GABA A receptor: relating occupancy to state functions. Molecular Pharmacology 98(4). MOLPHARM-AR-2020-000066. https://doi.org/10.1124/molpharm.120.000066.CrossRefGoogle ScholarPubMed
Akk, G, Li, P, Bracamontes, J, Wang, M, and Steinbach, JH (2011) Pharmacology of structural changes at the GABAA receptor transmitter binding site. British Journal of Pharmacology 162(4) 840. https://doi.org/10.1111/J.1476-5381.2010.01083.X.CrossRefGoogle ScholarPubMed
Amin, J, and Weiss, DS (1993) GABAA receptor needs two homologous domains of the & beta;-subunit for activation by GABA but not by pentobarbital. Nature 366(6455), 565–569. https://doi.org/10.1038/366565a0.CrossRefGoogle Scholar
Amundarain, MJ, Ribeiro, RP, Costabel, MD, and Giorgetti, A (2019) GABA A receptor family: overview on structural characterization. Future Medicinal Chemistry 11(3), 229–246. https://doi.org/10.4155/fmc-2018-0336.CrossRefGoogle ScholarPubMed
Ashby, JA, McGonigle, IV, Price, KL, Cohen, N, Comitani, F, Dougherty, DA, Molteni, C, and Lummis, SCR (2012) GABA binding to an insect GABA receptor: a molecular dynamics and mutagenesis study. Biophysical Journal 103(10), 2071–2081. https://doi.org/10.1016/j.bpj.2012.10.016.CrossRefGoogle Scholar
Bali, M, and Akabas, MH (2004) Defining the propofol binding site location on the GABAA receptor. Molecular Pharmacology 65(1), 68–76. https://doi.org/10.1124/mol.65.1.68.CrossRefGoogle ScholarPubMed
Bali, M, Jansen, M, and Akabas, MH (2009) Gaba-induced intersubunit conformational movement in the gabaa receptor α1m1-β2m3 transmembrane subunit interface: experimental basis for homology modeling of an intravenous anesthetic binding site. Journal of Neuroscience 29(10), 3083–3092. https://doi.org/10.1523/JNEUROSCI.6090-08.2009.CrossRefGoogle ScholarPubMed
Baptista-Hon, DT, Gulbinaite, S, and Hales, TG (2017) Loop G in the GABAA receptor α1 subunit influences gating efficacy. Journal of Physiology 595(5), 1725–1741. https://doi.org/10.1113/JP273752.CrossRefGoogle Scholar
Baptista-Hon, DT, Krah, A, Zachariae, U and Hales, TG (2016) A role for loop G in the α1 strand in GABAA receptor activation. The Journal of Physiology 00(19), 1–35. https://doi.org/10.1113/JP272463.Google Scholar
Barberis, A, Cherubini, E and Mozrzymas, JW (2000) Zinc inhibits miniature GABAergic currents by allosteric modulation of GABAA receptor gating. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 20(23), 8618–8627. https://doi.org/10.1523/JNEUROSCI.20-23-08618.2000.CrossRefGoogle ScholarPubMed
Barbour, B, and Häusser, M (1997). Intersynaptic diffusion of neurotransmitter. Trends in Neurosciences 20(9), 377–384. https://doi.org/10.1016/S0166-2236(96)20050-5.Google ScholarPubMed
Bar-Lev, DD, Degani-Katzav, N, Perelman, A, and Paas, Y (2011) Molecular dissection of Cl --selective cys-loop receptor points to components that are dispensable or essential for channel activity. Journal of Biological Chemistry 286(51), 43830–43841. https://doi.org/10.1074/jbc.M111.282715.CrossRefGoogle ScholarPubMed
Bartos, M, Corradi, J and Bouzat, C (2009) Structural basis of activation of cys-loop receptors: the extracellular–transmembrane interface as a coupling region. Molecular Neurobiology 40(3), 236–252. https://doi.org/10.1007/S12035-009-8084-X.CrossRefGoogle ScholarPubMed
Baumann, SW, Baur, R, and Sigel, E (2003) Individual properties of the two functional agonist sites in GABA(A) receptors. The Journal of Neuroscience 23(35), 11158–11166. https://doi.org/10.1523/JNEUROSCI.23-35-11158.2003.CrossRefGoogle ScholarPubMed
Baur, Rand Sigel, E (2003) On high- and low-affinity agonist sites in GABAA receptors. Journal of Neurochemistry 87(2), 325–332. https://doi.org/10.1046/j.1471-4159.2003.01982.x.CrossRefGoogle ScholarPubMed
Beato, M (2008) The time course of transmitter at glycinergic synapses onto motoneurons. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 28(29), 7412–7425. https://doi.org/10.1523/JNEUROSCI.0581-08.2008.CrossRefGoogle ScholarPubMed
Beaumont, K, Chilton, WS, Yamamura, HI, and Enna, SJ (1978). Muscimol binding in rat brain: Association with synaptic GABA receptors. Brain Research 148(1), 153–162. https://doi.org/10.1016/0006-8993(78)90385-2.CrossRefGoogle ScholarPubMed
Belelli, D, Lambert, JJ, Peters, JA, Wafford, K and Whiting, PJ (1997). The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid. Proceedings of the National Academy of Sciences of the United States of America, 94(20), 11031–11036. https://doi.org/10.1073/pnas.94.20.11031.CrossRefGoogle ScholarPubMed
Bera, AK, Chatav, M and Akabas, MH (2002) GABAA receptor M2-M3 loop secondary structure and changes in accessibility during channel gating. Journal of Biological Chemistry 277(45), 43002–43010. https://doi.org/10.1074/jbc.M206321200.CrossRefGoogle ScholarPubMed
Bianchi, MT, Botzolakis, EJ, Lagrange, AHand Macdonald, RL (2009) Benzodiazepine modulation of GABA(A) receptor opening frequency depends on activation context: a patch clamp and simulation study. Epilepsy Research 85(2–3), 212–220. https://doi.org/10.1016/J.EPLEPSYRES.2009.03.007.CrossRefGoogle ScholarPubMed
Bocquet, N, Nury, H, Baaden, M, Le Poupon, C, Changeux, J-P, Delarue, M, and Corringer, P-J (2009). X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457(7225), 111–114. https://doi.org/10.1038/nature07462.CrossRefGoogle Scholar
Bocquet, N, Prado De Carvalho, L, Cartaud, J, Neyton, J, Le Poupon, C, Taly, A, Grutter, T, Changeux, JP and Corringer, PJ (2007) A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature 445(7123), 116–119. https://doi.org/10.1038/nature05371.CrossRefGoogle ScholarPubMed
Boileau, AJ, Evers, AR, Davis, AF and Czajkowski, C (1999) Mapping the agonist binding site of the GABAA receptor: evidence for a beta-strand. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 19(12), 4847–4854. https://doi.org/10.1523/JNEUROSCI.19-12-04847.1999.CrossRefGoogle ScholarPubMed
Boileau, AJ, Li, T, Benkwitz, C, Czajkowski, C and Pearce, RA (2003) Effects of γ2S subunit incorporation on GABAA receptor macroscopic kinetics. Neuropharmacology 44(8), 1003–1012. https://doi.org/10.1016/S0028-3908(03)00114-X.CrossRefGoogle ScholarPubMed
Boileau, AJ, Newell, JG, and Czajkowski, C (2002) GABAA receptor β2Tyr97 and leu99 line the GABA-binding site. Journal of Biological Chemistry 277(4), 2931–2937. https://doi.org/10.1074/jbc.M109334200.CrossRefGoogle Scholar
Borghese, CM, Hicks, JA, Lapid, DJ, Trudell, JR and Harris, RA (2014)GABAA receptor transmembrane amino acids are critical for alcohol action: disulfide cross-linking and alkyl methanethiosulfonate labeling reveal relative location of binding sites. Journal of Neurochemistry 128(3), 363–375. https://doi.org/10.1111/jnc.12476.CrossRefGoogle ScholarPubMed
Bouron, A (2001) Modulation of spontaneous quantal release of neurotransmitters in the hippocampus. Progress in Neurobiology 63(6), 613–635. https://doi.org/10.1016/S0301-0082(00)00053-8.CrossRefGoogle ScholarPubMed
Brickley, SG and Mody, I (2012) Extrasynaptic GABAA receptors: their function in the cns and implications for disease. Neuron 73(1), 23–34. https://doi.org/10.1016/J.NEURON.2011.12.012.CrossRefGoogle ScholarPubMed
Brodzki, M, Michałowski, MA, Gos, M and Mozrzymas, JW (2020) Mutations of α1F45 residue of GABAA receptor loop G reveal its involvement in agonist binding and channel opening/closing transitions. Biochemical Pharmacology 177, 113917. https://doi.org/10.1016/j.bcp.2020.113917.CrossRefGoogle Scholar
Brodzki, M and Mozrzymas, JW (2022)GABAA receptor proline 273 at the interdomain interface of the β2 subunit regulates entry into desensitization and opening/closing transitions. Life Sciences 308, 120943. https://doi.org/10.1016/J.LFS.2022.120943.CrossRefGoogle ScholarPubMed
Brodzki, M, Rutkowski, R, Jatczak, M, Kisiel, M, Czyzewska, MM and Mozrzymas, JW (2016) Comparison of kinetic and pharmacological profiles of recombinant α1γ2L and α1β2γ2L GABAA receptors – a clue to the role of intersubunit interactions. European Journal of Pharmacology 784, 81–89. https://doi.org/10.1016/j.ejphar.2016.05.015.CrossRefGoogle Scholar
Bruns, D and Jahn, R (1995) Real-time measurement of transmitter release from single synaptic vesicles. Nature 377(6544), 62–65. https://doi.org/10.1038/377062A0.CrossRefGoogle ScholarPubMed
Brzdąk, P, Lebida, K, Wyroślak, M and Mozrzymas, JW (2023). GABAergic synapses onto SST and PV interneurons in the CA1 hippocampal region show cell-specific and integrin-dependent plasticity. Scientific Reports 13(1). https://doi.org/10.1038/S41598-023-31882-4.CrossRefGoogle ScholarPubMed
Carpenter, TS, Lau, EY and Lightstone, FC (2012) A role for loop F in modulating GABA binding affinity in the GABA A receptor. Journal of Molecular Biology 422(2), 310–323. https://doi.org/10.1016/j.jmb.2012.05.025.CrossRefGoogle Scholar
Carpenter, TS and Lightstone, FC (2016)An Electrostatic Funnel in the GABA-Binding Pathway. PLOS Computational Biology 12(4), e1004831. https://doi.org/10.1371/journal.pcbi.1004831.CrossRefGoogle ScholarPubMed
Castellano, D, Shepard, RD and Lu, W (2021) Looking for novelty in an “old” receptor: recent advances toward our understanding of gabaars and their implications in receptor pharmacology. Frontiers in Neuroscience 14, 1–15. https://doi.org/10.3389/fnins.2020.616298.CrossRefGoogle Scholar
Castellano, D, Wu, K, Keramidas, A, and Lu, W (2022) Shisa7-dependent regulation of gaba(a) receptor single-channel gating kinetics. J Neurosci 42(47), 8758–8766. https://doi.org/10.1523/jneurosci.0510-22.2022.CrossRefGoogle ScholarPubMed
Chang, Y and Weiss, DS (1999) Allosteric Activation Mechanism of the α1β2γ2 γ-Aminobutyric Acid Type A Receptor Revealed by Mutation of the Conserved M2 Leucine. Biophysical Journal, 77(5), 2542–2551.CrossRefGoogle Scholar
Chen, L, Wang, H, Vicini, S and Olsen, RW (2000). The gamma-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics. Proc Natl Acad Sci U S A 97(21), 11557–11562. https://doi.org/10.1073/pnas.190133497.CrossRefGoogle ScholarPubMed
Chen, Q, Wells, MM, Arjunan, P, Tillman, TS, Cohen, AE, Xu, Y and Tang, P (2018) Structural basis of neurosteroid anesthetic action on GABAAreceptors. Nature Communications 9(1), 1–10. https://doi.org/10.1038/s41467-018-06361-4.Google Scholar
Chen, ZW, Bracamontes, JR, Budelier, MM, Germann, AL, Shin, DJ, Kathiresan, K, Qian, MX, Manion, B, Cheng, WWL, Reichert, DE, Akk, G, Covey, DF and Evers, AS (2019) Multiple functional neurosteroid binding sites on gabaa receptors. PLoS Biology 17(3), 1–27. https://doi.org/10.1371/journal.pbio.3000157.CrossRefGoogle ScholarPubMed
Chen, Z-W, Manion, B, Townsend, R, Reichert, DE, Covey, DF, Steinbach, JH, Sieghart, W, Fuchs, K and Evers, AS (2012) Neurosteroid analog photolabeling of a site in the third transmembrane domain of the β3 subunit of the gabaa receptor. Molecular Pharmacology 82(3), 408–419. https://doi.org/10.1124/mol.112.078410.CrossRefGoogle Scholar
Chiara, DC, Dostalova, Z, Jayakar, SS, Zhou, X, Miller, KW and Cohen, JB (2012) Mapping general anesthetic binding site(s) in human α1β3γ- aminobutyric acid type a receptors with [ 3H]TDBzl-etomidate, a photoreactive etomidate analogue. Biochemistry 51(4), 836–847. https://doi.org/10.1021/BI201772M/SUPPL_FILE/BI201772M_SI_001.PDF.CrossRefGoogle Scholar
Chiu, CQ, Barberis, A and Higley, MJ (2019) Preserving the balance: diverse forms of long-term GABAergic synaptic plasticity. Nature Reviews Neuroscience 20(5), 272–281. https://doi.org/10.1038/s41583-019-0141-5.CrossRefGoogle ScholarPubMed
Chiu, CQ, Martenson, JS, Yamazak, M, Natsume, R, Sakimura, K, Tomita, S, Tavalin, SJ, and Higley, MJ (2018) input-specific nmdar-dependent potentiation of dendritic gabaergic inhibition. Neuron 97(2), 368https://doi.org/10.1016/j.neuron.2017.12.032.CrossRefGoogle ScholarPubMed
Clements, JD (1996) Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends in Neurosciences 19(5), 163–171. https://doi.org/10.1016/S0166-2236(96)10024-2.CrossRefGoogle ScholarPubMed
Colquhoun, D, Hawkes, AG and K, S. (1996). Joint distributions of apparent open and shut times of single-ion channels and maximum likelihood fitting of mechanisms. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 354, 2555–2590.Google Scholar
Colquhoun, D, Hatton, CJ and Hawkes, AG (2003) The quality of maximum likelihood estimates of ion channel rate constants. The Journal of Physiology 547( 3), 699–728. https://doi.org/10.1113/jphysiol.2002.034165.CrossRefGoogle ScholarPubMed
Colquhoun, D and Lape, R (2012)Allosteric coupling in ligand-gated ion channels. The Journal of General Physiology 140(6), 599–612. https://doi.org/10.1085/jgp.201210844.CrossRefGoogle ScholarPubMed
Colquhoun, D and Sigworth, FJ (1995) Fitting and statistical analysis of single channel records. In Single Channel Recording (ed. Sakmann, B. & Neher, E.), (pp. 483–587), New York and London: Plenum Press. https://doi.org/10.1007/978-1-4419-1229-9_19.Google Scholar
Comitani, F, Cohen, N, Ashby, J, Botten, D, Lummis, SCR and Molteni, C (2014) Insights into the binding of GABA to the insect RDL receptor from atomistic simulations: a comparison of models. Journal of Computer-Aided Molecular Design 28(1), 35–48. https://doi.org/10.1007/s10822-013-9704-0.CrossRefGoogle Scholar
Comitani, F, Limongelli, V and Molteni, C (2016) The free energy landscape of GABA binding to a pentameric ligand-gated ion channel and its disruption by mutations. Journal of Chemical Theory and Computation 12(7), 3398–3406. https://doi.org/10.1021/acs.jctc.6b00303.CrossRefGoogle ScholarPubMed
Cowgill, J, Fan, C, Haloi, N, Tobiasson, V, Zhuang, Y, Howard, RJ and Lindahl, E (2023)Structure and dynamics of differential ligand binding in the human ρ-type GABAA receptor. Neuron 111(21), 3450–3464.e5. https://doi.org/10.1016/J.NEURON.2023.08.006/ATTACHMENT/52392114-2D12-40AB-AECF-A1908D6FA0F1/MMC3.MP4.CrossRefGoogle Scholar
Curtis, DR, Duggan, AW, Felix, D and Johnston, GAR (1970) GABA, bicuculline and central inhibition. Nature. 226(5252), 1222–1224. https://doi.org/10.1038/2261222a0.CrossRefGoogle ScholarPubMed
Czajkowski, C and Wagner, DA (2001)Structure and dynamics of the GABA binding pocket: a narrowing cleft that constricts during activation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 21(1), 67–74. https://doi.org/10.1523/JNEUROSCI.21-01-00067.2001.Google Scholar
Czyzewska, MM and Mozrzymas, JW (2013) Monoterpene ??-thujone exerts a differential inhibitory action on GABAA receptors implicated in phasic and tonic GABAergic inhibition. European Journal of Pharmacology 702(1–3), 38–43. https://doi.org/10.1016/j.ejphar.2013.01.032.CrossRefGoogle ScholarPubMed
Davenport, CM, Rajappa, R, Katchan, L, Taylor, CR, Tsai, MC, Smith, CM, de Jong, JW, Arnold, DB, Lammel, S and Kramer, RH (2021) Relocation of an extrasynaptic GABA(A) receptor to inhibitory synapses freezes excitatory synaptic strength and preserves memory. Neuron 109(1), 123–134.e4. https://doi.org/10.1016/j.neuron.2020.09.037.CrossRefGoogle ScholarPubMed
de Luca, E, Ravasenga, T, Petrini, EM, Polenghi, A, Nieus, T, Guazzi, S and Barberis, A (2017) Inter-synaptic lateral diffusion of gabaa receptors shapes inhibitory synaptic currents. Neuron 95(1), 63–69.e5. https://doi.org/10.1016/j.neuron.2017.06.022.CrossRefGoogle ScholarPubMed
Dixon, CL, Harrison, NL, Lynch, JW, and Keramidas, A (2015) Zolpidem and eszopiclone prime a1b2y2 GABAA receptors for longer duration of activity. British Journal of Pharmacology 172(14), 3522–3536. https://doi.org/10.1111/bph.13142.CrossRefGoogle ScholarPubMed
Dixon, C, Sah, P, Lynch, JW, and Keramidas, A (2014) GABAA receptor α and γ subunits shape synaptic currents via different mechanisms. The Journal of Biological Chemistry 289(9), 5399–5411. https://doi.org/10.1074/jbc.M113.514695CrossRefGoogle ScholarPubMed
Downing, SS, Lee, YT, Farb, DH, and Gibbs, TT (2005) Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABA(A) receptors supports an allosteric model of modulation. British Journal of Pharmacology 145(7), 894–906. https://doi.org/10.1038/sj.bjp.0706251CrossRefGoogle ScholarPubMed
Eaton, MM, Cao, LQ, Chen, Z, Franks, NP, Evers, AS, and Akk, G. (2015) Mutational analysis of the putative high-affinity propofol binding site in human β3 homomeric GABAA receptors. Molecular Pharmacology 88(4), 736–745. https://doi.org/10.1124/MOL.115.100347CrossRefGoogle Scholar
Eaton, MM, Germann, LA, Arora, R, Cao, LQ, Gao, X, Shin, JD, Wu, A, Chiara, CD, Cohen, JB, Steinbach, JH, Evers, As, and Akk, G. (2016) Multiple Non-equivalent interfaces mediate direct activation of GABAA receptors by propofol. Current Neuropharmacology 14(7), 772–780. https://doi.org/10.2174/1570159X14666160202121319CrossRefGoogle ScholarPubMed
Eaton, MM, Lim, YB, Bracamontes, J, Steinbach, JH, and Akk, G (2012) Agonist-specific Conformational Changes in the Structure of the alpha1-gamma2 Subunit Interface of the GABAA Receptor. Molecular Pharmacology 82(2), 255–263. https://doi.org/10.1124/mol.112.077875CrossRefGoogle Scholar
Ernst, M, and Sieghart, W (2015) GABAA receptor subtypes: structural variety raises hope for new therapy concepts. E-Neuroforum 6(4), 97–103. https://doi.org/10.1007/s13295-015-0016-9CrossRefGoogle Scholar
Feng, HJ, and Forman, SA (2018) Comparison of αβδ and αβγ GABAAreceptors: allosteric modulation and identification of subunit arrangement by site-selective general anesthetics. Pharmacological Research 133, 289–300. https://doi.org/10.1016/j.phrs.2017.12.031CrossRefGoogle Scholar
Field, M, Dorovykh, V, Thomas, P, and Smart, TG (2021) Physiological role for GABAA receptor desensitization in the induction of long-term potentiation at inhibitory synapses. Nature Communications 12(1), 1–16. https://doi.org/10.1038/s41467-021-22420-9CrossRefGoogle ScholarPubMed
Förstera, B, Castro, PA, Moraga-Cid, G, and Aguayo, LG (2016) Potentiation of Gamma aminobutyric acid receptors (GABAAR) by ethanol: how are inhibitory receptors affected? Frontiers in Cellular Neuroscience 10 5), 1–17. https://doi.org/10.3389/fncel.2016.00114CrossRefGoogle ScholarPubMed
Franks, NP (2015) Structural comparisons of ligand-gated ion channels in open, closed, and desensitized states identify a novel propofol-binding site on mammalian γ-aminobutyric acid type A receptors. Anesthesiology 122(4), 787–794. https://doi.org/10.1097/ALN.0000000000000588CrossRefGoogle ScholarPubMed
Gafford, GM, Guo, JD, Flandreau, EI, Hazra, R., Rainnie, DG, and Ressler, KJ (2012) Cell-type specific deletion of GABA(A) α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction. Proceedings of the National Academy of Sciences of the United States of America 109(40), 16330–16335. https://doi.org/10.1073/PNAS.1119261109/SUPPL_FILE/PNAS.201119261SI.PDFCrossRefGoogle ScholarPubMed
Garifulina, A, Friesacher, T, Stadler, M, Zangerl-Plessl, EM, Ernst, M, Stary-Weinzinger, A, Willam, A, and Hering, S (2022) β subunits of GABAA receptors form proton-gated chloride channels: Insights into the molecular basis. Communications Biology 5(1) https://doi.org/10.1038/s42003-022-03720-2CrossRefGoogle ScholarPubMed
Germann, AL, Burbridge, AB, Pierce, SR, and Akk, G (2022) Activation of the Rat α1β2ε GABAA receptor by orthosteric and allosteric agonists. Biomolecules 12(7) https://doi.org/10.3390/biom12070868CrossRefGoogle ScholarPubMed
Germann, AL, Steinbach, JH, and Akk, G. (2018) Application of the Co-agonist concerted transition model to analysis of GABAA receptor properties. Current Neuropharmacology 17(9), 843–851. https://doi.org/10.2174/1570159x17666181206092418CrossRefGoogle Scholar
Ghosh, H, Auguadri, L, Battaglia, S, Simone Thirouin, Z, Zemoura, K, Messner, S, Acuna, MA, Wildner, H, Yevenes, GE, Dieter, A, Kawasaki, H, Hottiger, OM, Zeilhofer, HU, Fritschy, JM, and Tyagarajan, SK (2016) Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission. Nat Commun 7, 13365. https://doi.org/10.1038/ncomms13365CrossRefGoogle ScholarPubMed
Gielen, M, Barilone, N, and Corringer, PJ (2020) The desensitization pathway of GABAA receptors, one subunit at a time. Nature Communications 11(1) https://doi.org/10.1038/S41467-020-19218-6CrossRefGoogle ScholarPubMed
Gielen, M, and Corringer, PJ (2018) The dual-gate model for pentameric ligand-gated ion channels activation and desensitization. Journal of Physiology 596(10), 1873–1902. https://doi.org/10.1113/JP275100CrossRefGoogle ScholarPubMed
Gielen, M., Thomas, P., and Smart, TG (2015) The desensitization gate of inhibitory Cys-loop receptors. Nature Communications 6, 6829. https://doi.org/10.1038/ncomms7829CrossRefGoogle ScholarPubMed
Goldschen-Ohm, MP (2022) Benzodiazepine modulation of GABAA receptors: a mechanistic perspective. Biomolecules 12(12), 1784. https://doi.org/10.3390/BIOM12121784CrossRefGoogle ScholarPubMed
Goldschen-Ohm, MP, Haroldson, A., Jones, MV, and Pearce, RA (2014) A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABA A receptors. The Journal of General Physiology 144(1), 27–39. https://doi.org/10.1085/jgp.201411183CrossRefGoogle Scholar
Goldschen-ohm, MP, Wagner, DA, and Jones, MV (2011) Three arginines in the GABAA receptor binding pocket have distinct roles in the formation and stability of agonist- versus antagonist-bound complexes. Molecular Pharmacology 80(4), 647–656. https://doi.org/10.1124/mol.111.072033CrossRefGoogle ScholarPubMed
Gottschald Chiodi, C, Baptista-Hon, DT, Hunter, WN, and Hales, TG (2018) Amino acid substitutions in the human homomeric β3 GABAA receptor that enable activation by GABA. Journal of Biological Chemistry 294, jbc.RA118.006229. https://doi.org/10.1074/jbc.ra118.006229Google ScholarPubMed
Gurley, D, Amin, J, Ross, PC, Weiss, DS, and White, G (1995) Point mutations in the M2 region of the alpha, beta, or gamma subunit of the GABAA channel that abolish block by picrotoxin. Receptors & Channels 3(1), 13–20. https://europepmc.org/article/med/8589989Google ScholarPubMed
Haas, KF and Macdonald, RL (1999) GABA(A) receptor subunit γ2 and δ subtypes confer unique kinetic properties on recombinant GABA(A) receptor currents in mouse fibroblasts. Journal of Physiology 514(1), 27–45. https://doi.org/10.1111/j.1469-7793.1999.027af.x.CrossRefGoogle Scholar
Hájos, N., Nusser, Z., Rancz, EA, Freund, TF, and Mody, I. (2000) Cell type- and synapse-specific variability in synaptic GABAA receptor occupancy. The European Journal of Neuroscience 12(3), 810–818. https://doi.org/10.1046/J.1460-9568.2000.00964.XCrossRefGoogle ScholarPubMed
Hales, TG, Deeb, TZ, Tang, H, Bollan, KA, King, DP, Johnson, SJ, and Connolly, CN (2006) An asymmetric contribution to gamma-aminobutyric type A receptor function of a conserved lysine within TM2-3 of alpha1, beta2, and gamma2 subunits. The Journal of Biological Chemistry 281(25), 17034–17043. https://doi.org/10.1074/jbc.M603599200CrossRefGoogle ScholarPubMed
Han, W, Li, J, Pelkey, KA, Pandey, S, Chen, X, Wang, YX, Wu, K, Ge, L, Li, T, Castellano, D, Liu, C, Wu, LG, Petralia, RS, Lynch, JW, McBain, CJ, and Lu, W (2019) Shisa7 is a GABA(A) receptor auxiliary subunit controlling benzodiazepine actions. Science 366(6462), 246–250. https://doi.org/10.1126/science.aax5719CrossRefGoogle ScholarPubMed
Han, W, Shepard, RD, and Lu, W (2021) Regulation of GABAARs by transmembrane accessory proteins. Trends in Neurosciences 44(2), 152–165. https://doi.org/10.1016/j.tins.2020.10.011CrossRefGoogle ScholarPubMed
Hannan, S, Minere, M, Harris, J, Izquierdo, P, Thomas, P, Tench, B, and Smart, TG (2019) GABAAR isoform and subunit structural motifs determine synaptic and extrasynaptic receptor localisation. Neuropharmacology 107540. https://doi.org/10.1016/j.neuropharm.2019.02.022Google ScholarPubMed
Harris, KM, and Stevens, JK (1989) Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 9(8), 2982–2997. https://doi.org/10.1523/JNEUROSCI.09-08-02982.1989CrossRefGoogle ScholarPubMed
Harrison, NJ, and Lummis, SCR (2006a) Locating the carboxylate group of GABA in the homomeric rho GABA(A) receptor ligand-binding pocket. The Journal of Biological Chemistry 281(34), 24455–24461. https://doi.org/10.1074/jbc.M601775200CrossRefGoogle ScholarPubMed
Harrison, NJ, and Lummis, SCR (2006b) Molecular modeling of the GABA(C) receptor ligand-binding domain. Journal of Molecular Modeling 12(3), 317–324. https://doi.org/10.1007/S00894-005-0034-6CrossRefGoogle ScholarPubMed
Hartvig, L, Lükensmejer, B, Liljefors, T, and Dekermendjian, K (2002) Two conserved arginines in the extracellular N-terminal domain of the GABAA receptor α5 subunit are crucial for receptor function. Journal of Neurochemistry 75(4), 1746–1753. https://doi.org/10.1046/j.1471-4159.2000.0751746.xCrossRefGoogle Scholar
Hausrat, TJ, Muhia, M, Gerrow, K, Thomas, P, Hirdes, W, Tsukita, S, Heisler, FF, Herich, L, Dubroqua, S, Breiden, P, Feldon, J, Schwarz, JR, Yee, BK, Smar, TG, Triller, A, and Kneussel, M (2015) Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory. Nat Commun 6, 6872. https://doi.org/10.1038/ncomms7872CrossRefGoogle ScholarPubMed
Hawkes, AG, Jalali, A, and Colquhoun, D (1992) Asymptotic distributions of apparent open times and shut times in a single channel record allowing for the omission of brief events. Philosophical Transactions of the Royal Society of London. Series B Biological Sciences 337(1282), 383–404. https://doi.org/10.1098/rstb.1992.0116Google Scholar
Hernandez, CC, Kong, W, Hu, N, Zhang, Y, Shen, W, Jackson, L, Liu, X, Jiang, Y, and Macdonald, RL (2017) Altered channel conductance states and gating of GABAA receptors by a pore mutation linked to Dravet syndrome. ENeuro 4(1) https://doi.org/10.1523/ENEURO.0251-16.2017CrossRefGoogle ScholarPubMed
Hernandez, CC, and Macdonald, RL (2019) A Structural look at GABA A receptor mutations linked to epilepsy syndromes. In Brain Research (Vol. 1714, pp. 234–247) Elsevier B.V. https://doi.org/10.1016/j.brainres.2019.03.004Google Scholar
Hibbs, RE, and Gouaux, E (2011) Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474(7349), 54–60. https://doi.org/10.1038/nature10139CrossRefGoogle Scholar
Hilf, RJC, and Dutzler, R (2008) X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452(7185), 375–379. https://doi.org/10.1038/nature06717CrossRefGoogle ScholarPubMed
Hilf, RJC, and Dutzler, R (2009) Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457(7225), 115–118. https://doi.org/10.1038/nature07461CrossRefGoogle ScholarPubMed
Holden, JH, and Czajkowski, C (2002) Different residues in the GABAA receptor α1T60-α1K70 region mediate GABA and SR-95531 actions. Journal of Biological Chemistry 277(21), 18785–18792. https://doi.org/10.1074/jbc.M111778200CrossRefGoogle ScholarPubMed
Horenstein, J, Wagner, DA, Czajkowski, C, and Akabas, MH (2001) Protein mobility and GABA-induced conformational changes in GABA(A) receptor pore-lining M2 segment. Nature Neuroscience 4(5), 477–485. https://doi.org/10.1038/87425CrossRefGoogle ScholarPubMed
Hosie, AM, Clarke, L, da Silva, H, and Smart, TG (2009) Conserved site for neurosteroid modulation of GABAA receptors. Neuropharmacology 56(1), 149–154. https://doi.org/10.1016/J.NEUROPHARM.2008.07.050CrossRefGoogle Scholar
Hosie, AM, Wilkins, ME, Da Silva, HMA, and Smart, TG (2006) Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444(7118), 486–489. https://doi.org/10.1038/nature05324CrossRefGoogle ScholarPubMed
Howard, RJ (2021) Elephants in the dark: insights and incongruities in pentameric ligand-gated ion channel models. Journal of Molecular Biology 433(17), 167128. https://doi.org/10.1016/j.jmb.2021.167128CrossRefGoogle ScholarPubMed
Huang, X, Shaffer, PL, Ayube, S, Bregman, H, Chen, H, Lehto, SG, Luther, JA, Matson, DJ, McDonough, SI, Michelsen, K, Plant, MH, Schneider, S, Simard, JR, Teffera, Y, Yi, S, Zhang, M, DiMauro, EF, and Gingras, J (2017) Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators. Nature Structural & Molecular Biology 24(2), 108–113. https://doi.org/10.1038/nsmb.3329CrossRefGoogle ScholarPubMed
Jadey, S, and Auerbach, A (2012) An integrated catch-and-hold mechanism activates nicotinic acetylcholine receptors. The Journal of General Physiology 140(1), 17–28. https://doi.org/10.1085/jgp.201210801CrossRefGoogle ScholarPubMed
Jatczak-Śliwa, M, Kisiel, M, Czyzewska, MM, Brodzki, M, and Mozrzymas, JW (2020) GABAA receptor β2E155 residue located at the agonist-binding site is involved in the receptor gating. Frontiers in Cellular Neuroscience 14 2), 1–18. https://doi.org/10.3389/fncel.2020.00002CrossRefGoogle ScholarPubMed
Jatczak-Śliwa, M, Terejko, K, Brodzki, M, Michałowski, MAMA, Czyzewska, MMM, Nowicka, JMJM, Andrzejczak, A, Srinivasan, R, and Mozrzymas, JWJW (2018) Distinct Modulation of Spontaneous and GABA-Evoked Gating by Flurazepam Shapes Cross-Talk Between Agonist-Free and Liganded GABAA Receptor Activity. Frontiers in Cellular Neuroscience 12(8), 1–18. https://doi.org/10.3389/fncel.2018.00237CrossRefGoogle Scholar
Jayakar, SS, Chiara, DC, Zhou, X, Wu, B, Bruzik, KS, Miller, KW, and Cohen, JB (2020) Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABAA) receptors. The Journal of Biological Chemistry 295(33), 11495–11512. https://doi.org/10.1074/jbc.RA120.013452CrossRefGoogle Scholar
Jayakar, SS, Zhou, X, Chiara, DC, Dostalova, Z, Savechenkov, PY, Bruzik, KS, Dailey, WP, Miller, KW, Eckenhoff, RG, and Cohen, JB (2014) Multiple propofol-binding sites in a γ-aminobutyric acid type a receptor (GABAAR) identified using a photoreactive propofol analog. Journal of Biological Chemistry 289(40), 27456–27468. https://doi.org/10.1074/jbc.M114.581728CrossRefGoogle Scholar
Jayakar, SS, Zhou, X, Chiara, DC, Jarava-Barrera, C, Savechenkov, PY, Bruzik, KS, Tortosa, M, Miller, KW, and Cohen, JB (2019) Identifying drugs that bind selectively to intersubunit general anesthetic sites in the α1β3γ2 GABA A R transmembrane domain. Molecular Pharmacology 02115(6), https://doi.org/10.1124/mol.118.114975Google Scholar
Jiang, X, Shu, H-J, Krishnan, K, Qian, M, Taylor, AA, Covey, DF, Zorumski, CF, and Mennerick, S (2016) A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition. Neuropharmacology 108, 193–206. https://doi.org/10.1016/j.neuropharm.2016.04.031CrossRefGoogle ScholarPubMed
Jonas, P (1995) Fast application of agonists to isolated membrane patches. In Sakmann, B. & Neher, E. (Eds.), Single-Channel Recording (pp. 231–243) Springer US.CrossRefGoogle Scholar
Jones, MV, and Westbrook, GL (1995) Desensitized states prolong GABAA channel responses to brief agonist pulses. Neuron 15(1), 181–191. https://doi.org/10.1016/0896-6273(95)90075-6CrossRefGoogle ScholarPubMed
Kaczor, PT, Michałowski, MA, and Mozrzymas, JW (2022) α 1 Proline 277 Residues Regulate GABAAR Gating through M2-M3 Loop Interaction in the Interface Region. ACS Chemical Neuroscience 13(21), 3044–3056. https://doi.org/10.1021/acschemneuro.2c00401CrossRefGoogle ScholarPubMed
Kaczor, PT, Wolska, AD, and Mozrzymas, JW (2021) α1 subunit histidine 55 at the interface between extracellular and transmembrane domains affects preactivation and desensitization of the GABAA receptor. ACS Chemical Neuroscience. https://doi.org/10.1021/acschemneuro.0c00781CrossRefGoogle Scholar
Kaila, K, Voipio, J, Paalasmaa, P, Pasternack, M, and Deisz, RA (1993) The role of bicarbonate in GABAA receptor-mediated IPSPs of rat neocortical neurones. The Journal of Physiology 464(1), 273–289. https://doi.org/10.1113/JPHYSIOL.1993.SP019634CrossRefGoogle ScholarPubMed
Kasaragod, VB, Malinauskas, T, Wahid, AA, Lengyel, J, Knoflach, F, Hardwick, SW, Jones, CF, Chen, WN, Lucas, X, El Omari, K, Chirgadze, DY, Aricescu, AR, Cecere, G, Hernandez, MC, and Miller, PS (2023) The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors. Nature Structural & Molecular Biology 2023, 1–11. https://doi.org/10.1038/s41594-023-01133-1Google Scholar
Kasaragod, VB, Mortensen, M, Hardwick, SW, Wahid, AA, Dorovykh, V, Chirgadze, DY, Smart, TG, and Miller, PS (2022) Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors. Nature 123. https://doi.org/10.1038/s41586-022-04402-zGoogle Scholar
Kash, TL, Dizon, M-JF, Trudell, JR, and Harrison, NL (2004b) Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation. Journal of Biological Chemistry 279(6), 4887–4893. https://doi.org/10.1074/jbc.M311441200CrossRefGoogle ScholarPubMed
Kash, TL, Jenkins, A, Kelley, JC, Trudell, JR, and Harrison, NL (2003) Coupling of agonist binding to channel gating in the GABA(A) receptor. Nature 421(6920), 272–275. https://doi.org/10.1038/nature01280CrossRefGoogle ScholarPubMed
Kash, TL, Kim, T, Trudell, JR, and Harrison, NL (2004a) Evaluation of a proposed mechanism of ligand-gated ion channel activation in the GABA. Neuroscience Letters 371(2–3), 230–234. https://doi.org/10.1016/j.neulet.2004.09.002CrossRefGoogle Scholar
Keramidas, A, Kash, TL, and Harrison, NL (2006) The Pre-M1 Segment of the α1 Subunit is a Transduction Element in the Activation of the GABA-A Receptor. The Journal of Physiology 99(Pt 1), 1–33. https://doi.org/10.1113/jphysiol.2005.102756Google Scholar
Khatri, A, Sedelnikova, A, and Weiss, DS (2009) Structural rearrangements in loop F of the GABA receptor signal ligand binding, not channel activation. Biophysical Journal 96(1), 45–55. https://doi.org/10.1016/j.bpj.2008.09.011CrossRefGoogle Scholar
Khayenko, V, and Maric, HM (2019) Targeting GABAAR-Associated Proteins: New Modulators, Labels and Concepts. Frontiers in Cellular Neuroscience 12, 162. https://doi.org/10.3389/fnmol.2019.00162Google Scholar
Kim, JJ, Gharpure, A, Teng, J, Zhuang, Y, Howard, RJ, Zhu, S, Noviello, CM, Walsh, RM, Lindahl, E, and Hibbs, RE (2020) Shared structural mechanisms of general anaesthetics and benzodiazepines. Nature 585(7824), 303–308. https://doi.org/10.1038/s41586-020-2654-5CrossRefGoogle ScholarPubMed
Kim, JJ, and Hibbs, RE (2021) Direct Structural Insights into GABAA Receptor Pharmacology. Trends in Biochemical Sciences 46(6), 502–517. https://doi.org/10.1016/j.tibs.2021.01.011CrossRefGoogle Scholar
Kisiel, M, Jatczak, M, Brodzki, M, and Mozrzymas, JW (2018) Spontaneous activity, singly bound states and the impact of alpha 1 Phe64 mutation on GABA A R gating in the novel kinetic model based on the single-channel recordings. Neuropharmacology 131, 453–474. https://doi.org/10.1016/j.neuropharm.2017.11.030CrossRefGoogle Scholar
Kisiel, M, Jatczak-Śliwa, M, and Mozrzymas, JW (2019) Protons modulate gating of recombinant α1β2γ2 GABAA receptor by affecting desensitization and opening transitions. Neuropharmacology 146(10), 300–315. https://doi.org/10.1016/j.neuropharm.2018.10.016CrossRefGoogle ScholarPubMed
Kittler, JT, and Moss, SJ (2003) Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition. Current Opinion in Neurobiology 13(3), 341–347. https://doi.org/10.1016/s0959-4388(03)00064-3CrossRefGoogle ScholarPubMed
Kloda, JH, and Czajkowski, C. (2007) Agonist-, antagonist-, and benzodiazepine-induced structural changes in the alpha1 Met113-Leu132 region of the GABAA receptor. Molecular Pharmacology 71(2), 483–493. https://doi.org/10.1124/MOL.106.028662CrossRefGoogle ScholarPubMed
Kłopotowski, K., Czyżewska, MM, and Mozrzymas, JW (2021) Glycine substitution of α1F64 residue at the loop D of GABAA receptor impairs gating - Implications for importance of binding site-channel gate linker rigidity. Biochemical Pharmacology 192. https://doi.org/10.1016/J.BCP.2021.114668CrossRefGoogle ScholarPubMed
Kłopotowski, K., Michałowski, MA, Gos, M, Mosiądz, D, Czyżewska, MM, and Mozrzymas, JW (2023) Mutation of valine 53 at the interface between extracellular and transmembrane domains of the β2 principal subunit affects the GABAA receptor gating. European Journal of Pharmacology 947, 175664. https://doi.org/10.1016/j.ejphar.2023.175664CrossRefGoogle Scholar
Korol, SV, Jin, Z, Jin, Y, Bhandage, AK, Tengholm, A, Gandasi, NR, Barg, S, Espes, D, Carlsson, PO, Laver, D, and Birnir, B (2018) Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells. EBioMedicine 30, 273–282. https://doi.org/10.1016/J.EBIOM.2018.03.014CrossRefGoogle ScholarPubMed
Krasowski, MD, Nishikawa, K, Nikolaeva, N, Lin, A, and Harrison, NL (2001) Methionine 286 in transmembrane domain 3 of the GABAA receptor B subunit controls a binding cavity for propofol and other alkylphenol general anesthetics. Neuropharmacology 41(8), 952–964. https://doi.org/10.1016/S0028-3908(01)00141-1CrossRefGoogle Scholar
Krishek, B, Moss, S, and Smart, T (1998) Interaction of H+ and Zn2+ on recombinant and native rat neuronal GABAA receptors. Journal of Physiology 507(3), 639–652. http://discovery.ucl.ac.uk/22040/CrossRefGoogle Scholar
Krishek, BJ, Amato, A, Connolly, CN, Moss, SJ, T, T. G. S, and Smart, TG (1996) Proton sensitivity of the GABAA receptor is associated with the receptor subunit composition. Journal of Physiology 431–443.CrossRefGoogle ScholarPubMed
Krogsgaard-Larsen, P, Falch, E, Schousboe, A, Curtist, DR, and Lodget, D (1980) Piperidine-4-sulphonic Acid, a New Specific GAB A Agonist. Journal of Neurochemistry 34(3), 756–759. https://doi.org/10.1111/J.1471-4159.1980.TB11211.XCrossRefGoogle Scholar
Laha, KT, and Tran, PN (2013) Multiple tyrosine residues at the GABA binding pocket influence surface expression and mediate kinetics of the GABAA receptor. Journal of Neurochemistry 124(2), 200–209. https://doi.org/10.1111/jnc.12083CrossRefGoogle ScholarPubMed
Laha, KT, and Wagner, DA (2011) A state-dependent salt-bridge interaction exists across the β/α intersubunit interface of the GABAA receptor. Molecular Pharmacology 79(4), 662–671. https://doi.org/10.1124/mol.110.068619CrossRefGoogle ScholarPubMed
Lape, R, Colquhoun, D, and Sivilotti, LG (2008) On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454(7205), 722–727. https://doi.org/10.1038/nature07139CrossRefGoogle ScholarPubMed
Laverty, D, Desai, R, Uchański, T, Masiulis, S, Stec, WJ, Malinauskas, T, Zivanov, J, Pardon, E, Steyaert, J, Miller, KW, and 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/s41586-018-0833-4CrossRefGoogle Scholar
Laverty, D, Thomas, P, Field, M, Andersen, OJ, Gold, MG, Biggin, PC, Gielen, M, and Smart, TG (2017) Crystal structures of a GABA A -receptor chimera reveal new endogenous neurosteroid-binding sites. Nature Structural and Molecular Biology 24(11), 977–985. https://doi.org/10.1038/nsmb.3477CrossRefGoogle ScholarPubMed
Legesse, DH, Fan, C, Teng, J, Zhuang, Y, Howard, RJ, Noviello, CM, Lindahl, E, and Hibbs, RE (2023) Structural insights into opposing actions of neurosteroids on GABAA receptors. Nature Communications 14(1), 1–13. https://doi.org/10.1038/s41467-023-40800-1CrossRefGoogle Scholar
Lema, GMCC, and Auerbach, A (2006) Modes and models of GABAA receptor gating. Journal of Physiology 572(1), 183–200. https://doi.org/10.1016/j.yhbeh.2006.02.010CrossRefGoogle Scholar
Lévi, S, Le Roux, N, Eugène, E, and Poncer, JC (2015) Benzodiazepine ligands rapidly influence GABAA receptor diffusion and clustering at hippocampal inhibitory synapses. Neuropharmacology 88, 199–208. https://doi.org/10.1016/j.neuropharm.2014.06.002CrossRefGoogle ScholarPubMed
Li, GD, Chiara, DC, Cohen, JB, and Olsen, RW (2010) Numerous classes of general anesthetics inhibit etomidate binding to γ-aminobutyric acid type A (GABAA) receptors. Journal of Biological Chemistry 285(12), 8615–8620. https://doi.org/10.1074/jbc.M109.074708CrossRefGoogle ScholarPubMed
Li, GD, Chiara, DC, Sawyer, GW, Husain, SS, Olsen, RW, and Cohen, JB (2006) Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 26(45), 11599–11605. https://doi.org/10.1523/JNEUROSCI.3467-06.2006CrossRefGoogle ScholarPubMed
Liu, S, Xu, L, Guan, F, Liu, Y-TT, Cui, Y, Zhang, Q, Zheng, X, Bi, G-QQ, Zhou, ZH, Zhang, X, and Ye, S (2018) Cryo-EM structure of the human α5β3 GABAA receptor. Cell Research 28(9), 958–961. https://doi.org/10.1038/s41422-018-0077-8CrossRefGoogle Scholar
Loebrich, S, Bähring, R, Katsuno, T, Tsukita, S, and Kneussel, M (2006) Activated radixin is essential for GABAA receptor alpha5 subunit anchoring at the actin cytoskeleton. EMBO Journal 25(5), 987–999. https://doi.org/10.1038/sj.emboj.7600995CrossRefGoogle ScholarPubMed
Lummis, SCR (2009) Locating GABA in GABA receptor binding sites. Biochemical Society Transactions 37(6), 1343–1346. https://doi.org/10.1042/BST0371343CrossRefGoogle ScholarPubMed
Lummis, SCR, Beene, DL, Harrison, NJ, Lester, HA, and Dougherty, DA (2005) A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor. Chemistry & Biology 12(9), 993–997. https://doi.org/10.1016/J.CHEMBIOL.2005.06.012CrossRefGoogle ScholarPubMed
Lummis, SCR, Harrison, NJ, Wang, J, Ashby, JA, Millen, KS, Beene, DL, and Dougherty, DA (2012) Multiple Tyrosine Residues Contribute to GABA Binding in the GABA(C) Receptor Binding Pocket. ACS Chemical Neuroscience 3(3), 186–192. https://doi.org/10.1021/CN200103NCrossRefGoogle ScholarPubMed
Lummis, SCR, McGonigle, I, Ashby, JA, and Dougherty, DA. (2011) Two amino acid residues contribute to a cation-π binding interaction in the binding site of an insect GABA receptor. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 31(34), 12371–12376. https://doi.org/10.1523/JNEUROSCI.1610-11.2011CrossRefGoogle ScholarPubMed
Maldifassi, MC, Baur, R, and Sigel, E (2016) Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital. Neuropharmacology 105, 207–214. https://doi.org/10.1016/j.neuropharm.2016.01.003CrossRefGoogle ScholarPubMed
Maramai, S, Benchekroun, M, Ward, SE, and Atack, JR (2020) Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update. Journal of Medicinal Chemistry 63(7), 3425–3446. https://doi.org/10.1021/acs.jmedchem.9b01312CrossRefGoogle ScholarPubMed
Maric, D, Maric, I, Wen, X, Fritschy, JM, Sieghart, W, Barker, JL, and Serafini, R (1999) GABAA receptor subunit composition and functional properties of Cl- channels with differential sensitivity to zolpidem in embryonic rat hippocampal cells. Journal of Neuroscience 19(12), 4921–4937. papers://9648de94-53eb-41f8-8282-2a8285ba1a70/Paper/p1508CrossRefGoogle ScholarPubMed
Marsden, KC, Beattie, JB, Friedenthal, J, and Carroll, RC (2007) NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABAAReceptors. The Journal of Neuroscience 27(52), 14326–14337. https://doi.org/10.1523/jneurosci.4433-07.2007CrossRefGoogle Scholar
Marsden, KC, Shemesh, A, Bayer, KU, and Carroll, RC (2010) Selective translocation of Ca2+/calmodulin protein kinase IIalpha (CaMKIIalpha) to inhibitory synapses. Proceedings of the National Academy of Sciences of the United States of America 107(47), 20559–20564. https://doi.org/10.1073/pnas.1010346107CrossRefGoogle ScholarPubMed
Masiulis, S, Desai, R, Uchański, T, Serna Martin, I, Laverty, D, Karia, D, Malinauskas, T, Zivanov, J, Pardon, E, Kotecha, A, Steyaert, J, Miller, KW, and Aricescu, AR (2019) GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature 565(7740), 454–459. https://doi.org/10.1038/s41586-018-0832-5CrossRefGoogle ScholarPubMed
Maynard, SA, and Triller, A (2019) Inhibitory Receptor Diffusion Dynamics. Frontiers in Molecular Neuroscience 12, 313. https://doi.org/10.3389/fnmol.2019.00313CrossRefGoogle ScholarPubMed
McKernan, RM, and Whiting, PJ (1996) Which GABAA-receptor subtypes really occur in the brain? Trends in Neurosciences 19(4), 139–143. https://doi.org/10.1016/S0166-2236(96)80023-3CrossRefGoogle ScholarPubMed
Melis, C, Lummis, SCR, and Molteni, C (2008) Molecular dynamics simulations of GABA binding to the GABAC receptor: the role of Arg104. Biophysical Journal 95(9), 4115–4123. https://doi.org/10.1529/BIOPHYSJ.107.127589CrossRefGoogle Scholar
Mercado, J (2006) Charged Residues in the 1 and beta2 Pre-M1 Regions Involved in GABAA Receptor Activation. Journal of Neuroscience 26(7), 2031–2040. https://doi.org/10.1523/JNEUROSCI.4555-05.2006CrossRefGoogle Scholar
Merlaud, Z, Marques, X, Russeau, M, Saade, U, Tostain, M, Moutkine, I, Gielen, M, Corringer, PJ, and Lévi, S (2022) Conformational state-dependent regulation of GABAA receptor diffusion and subsynaptic domains. IScience 25(11) https://doi.org/10.1016/j.isci.2022.105467CrossRefGoogle ScholarPubMed
Michałowski, MA, Czyżewska, MM, Iżykowska, I, and Mozrzymas, JW (2021) The β2 subunit E155 residue as a proton sensor at the binding site on GABA type A receptors. European Journal of Pharmacology 906(12), 174293. https://doi.org/10.1016/j.ejphar.2021.174293CrossRefGoogle ScholarPubMed
Michałowski, MA, Kraszewski, S, and Mozrzymas, JW (2017) Binding site opening by loop C shift and chloride ion-pore interaction in the GABA A receptor model. Physical Chemistry Chemical Physics 19(21), 13664–13678. https://doi.org/10.1039/C7CP00582BCrossRefGoogle Scholar
Mihalik, B, Pálvölgyi, A, Bogár, F, Megyeri, K, Ling, I, Barkóczy, J, Bartha, F, Martinek, TA, Gacsályi, I, and Antoni, FA (2017) Loop-F of the α-subunit determines the pharmacologic profile of novel competitive inhibitors of GABAA receptors. European Journal of Pharmacology 798(11), 129–136. https://doi.org/10.1016/j.ejphar.2017.01.033CrossRefGoogle Scholar
Miko, A, Werby, E, Sun, H, Healey, J, and Zhang, L (2004) A TM2 residue in the β1 subunit determines spontaneous opening of homomeric and heteromeric γ-aminobutyric acid-gated ion channels. Journal of Biological Chemistry 279(22), 22833–22840. https://doi.org/10.1074/jbc.M402577200CrossRefGoogle ScholarPubMed
Miller, C (1989) Genetic manipulation of ion channels: A new approach to structure and mechanism. Neuron 2(3), 1195–1205. https://doi.org/10.1016/0896-6273(89)90304-8CrossRefGoogle ScholarPubMed
Miller, PS, and Aricescu, AR (2014) Crystal structure of a human GABAA receptor. Nature 512(7514), 270–275. https://doi.org/10.1038/nature13293CrossRefGoogle ScholarPubMed
Miller, PS, Scott, S, Masiulis, S, De Colibus, L, Pardon, E, Steyaert, J, and Aricescu, AR (2017) Structural basis for GABA A receptor potentiation by neurosteroids. Nature Structural and Molecular Biology 24(11), 986–992. https://doi.org/10.1038/nsmb.3484CrossRefGoogle ScholarPubMed
Mohamad, FH, and Has, ATC (2019) The α5-Containing GABAA Receptors—a Brief Summary. Journal of Molecular Neuroscience 67(2), 343–351. https://doi.org/10.1007/s12031-018-1246-4CrossRefGoogle ScholarPubMed
Mortensen, M, Wafford, KA, Wingrove, P, and Ebert, B (2003) Pharmacology of GABAA receptors exhibiting different levels of spontaneous activity. European Journal of Pharmacology 476(1–2), 17–24. https://doi.org/10.1016/S0014-2999(03)02125-3CrossRefGoogle ScholarPubMed
Mortensen, M, Xu, Y, Shehata, MA, Krall, J, Ernst, M, Frølund, B, and Smart, TG (2023) Pregnenolone sulfate analogues differentially modulate GABAA receptor closed/desensitised states. British Journal of Pharmacology https://doi.org/10.1111/bph.16143CrossRefGoogle ScholarPubMed
Mozrzymas, JW (2004) Dynamism of GABAA receptor activation shapes the “personality” of inhibitory synapses. Neuropharmacology 47(7), 945–960. https://doi.org/10.1016/j.neuropharm.2004.07.003CrossRefGoogle ScholarPubMed
Mozrzymas, JW, Barberis, A, Mercik, K, and Zarnowska, ED (2003) Binding Sites, Singly Bound States, and Conformation Coupling Shape GABA-Evoked Currents. Journal of Neurophysiology 89(2), 871–883. https://doi.org/10.1152/jn.00951.2002CrossRefGoogle ScholarPubMed
Mozrzymas, JW, Barberis, A, Michalak, K, and Cherubini, E (1999) Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABA(A) receptors. Journal of Neuroscience 19(7), 2474–2488. https://doi.org/10.1523/jneurosci.19-07-02474.1999CrossRefGoogle Scholar
Mozrzymas, JW, Barberis, A, and Vicini, S (2007b) GABAergic currents in RT and VB thalamic nuclei follow kinetic pattern of alpha3- and alpha1-subunit-containing GABAA receptors. The European Journal of Neuroscience 26(3), 657–665. https://doi.org/10.1111/J.1460-9568.2007.05693.XCrossRefGoogle ScholarPubMed
Mozrzymas, JW, Wójtowicz, T, Piast, M, Lebida, K, Wyrembek, P, and Mercik, K (2007a) GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons. The Journal of Physiology 585( 1), 29–46. https://doi.org/10.1113/jphysiol.2007.143602CrossRefGoogle ScholarPubMed
Mukhtasimova, N, Lee, WY, Wang, H-L, and Sine, SM (2009) Detection and trapping of intermediate states priming nicotinic receptor channel opening. Nature 459(7245), 451–454. https://doi.org/10.1038/nature07923CrossRefGoogle ScholarPubMed
Muroi, Y, Czajkowski, C, and Jackson, MB (2006) Local and global ligand-induced changes in the structure of the GABA A receptor. Biochemistry 45(23), 7013–7022. https://doi.org/10.1021/bi060222vCrossRefGoogle ScholarPubMed
Muroi, Y, Theusch, CM, Czajkowski, C, and Jackson, MB (2009) Distinct structural changes in the GABAA receptor elicited by pentobarbital and GABA. Biophysical Journal 96(2), 499–509. https://doi.org/10.1016/j.bpj.2008.09.037CrossRefGoogle ScholarPubMed
Naffaa, MM, Absalom, N, Raja Solomon, V, Chebib, M, Hibbs, DE, and Hanrahan, JR (2016) Investigating the Role of Loop C Hydrophilic Residue ‘T244’ in the Binding Site of ρ1 GABAC Receptors via Site Mutation and Partial Agonism. PLoS ONE 11(5), e0156618. https://doi.org/10.1371/JOURNAL.PONE.0156618CrossRefGoogle Scholar
Naffaa, MM, Hibbs, DE, Chebib, M, and Hanrahan, JR (2022) Roles of hydrophilic residues in GABA binding site of GABA-ρ1 receptor explain the addition/inhibition effects of competitive ligands. Neurochemistry International 153, 105258. https://doi.org/10.1016/J.NEUINT.2021.105258CrossRefGoogle ScholarPubMed
Nakamura, Y, Darnieder, LM, Deeb, TZ, and Moss, SJ (2015) Regulation of GABA A Rs by phosphorylation. Advances in Pharmacology 72, 97-146. https://doi.org/10.1016/bs.apha.2014.11.008CrossRefGoogle Scholar
Nakane, T, Kotecha, A, Sente, A, Mcmullan, G, Masiulis, S, Brown, PMGE, Grigoras, IT, Malinauskaite, L, Malinauskas, T, Miehling, J, Uchański, T, Yu, L, Karia, D, Pechnikova, EV, De Jong, E, Keizer, J, Bischoff, M, Mccormack, J, Tiemeijer, P, … Scheres, HW (2020) Single-particle cryo-EM at atomic resolution. Nature 587. https://doi.org/10.1038/s41586-020-2829-0CrossRefGoogle ScholarPubMed
Newell, JG, and Czajkowski, C (2003) The GABAA receptor α1 subunit Pro174–Asp191 segment is involved in GABA binding and channel gating. Journal of Biological Chemistry 278(15), 13166–13172. https://doi.org/10.1074/jbc.M211905200CrossRefGoogle ScholarPubMed
Newell, JG, McDevitt, RA, and Czajkowski, C (2004) Mutation of glutamate 155 of the GABAA receptor 2 subunit produces a spontaneously open channel: a trigger for channel activation. Journal of Neuroscience 24(50), 11226–11235. https://doi.org/10.1523/JNEUROSCI.3746-04.2004CrossRefGoogle Scholar
Nors, JW, Gupta, S, and Goldschen-Ohm, MP (2021) A critical residue in the α1M2–M3 linker regulating mammalian GABAA receptor pore gating by diazepam. ELife 10, 1–21. https://doi.org/10.7554/eLife.64400CrossRefGoogle ScholarPubMed
Nourmahnad, A, Stern, AT, Hotta, M, Stewart, DS, Ziemba, AM, Szabo, A, and Forman, SA (2016) Tryptophan and cysteine mutations in M1 helices of α1β3γ2L γ-aminobutyric acid type A receptors indicate distinct intersubunit sites for four intravenous anesthetics and one orphan site. Anesthesiology 125(6), 1144–1158. https://doi.org/10.1097/ALN.0000000000001390CrossRefGoogle ScholarPubMed
Noviello, CM, Gharpure, A, Mukhtasimova, N, Cabuco, R, Baxter, L, Borek, D, Sine, SM, and Hibbs, RE (2021) Structure and gating mechanism of the α7 nicotinic acetylcholine receptor. Cell 184(8), 2121–2134.e13. https://doi.org/10.1016/j.cell.2021.02.049CrossRefGoogle ScholarPubMed
Noviello, CM, Kreye, J, Teng, J, Prüss, H, and Hibbs, RE (2022) Structural mechanisms of GABAA receptor autoimmune encephalitis. Cell 185(14), 2469–2477.e13. https://doi.org/10.1016/J.CELL.2022.06.025CrossRefGoogle ScholarPubMed
Olsen, RW (2018) GABAAreceptor: positive and negative allosteric modulators. Neuropharmacology 136, 10–22. https://doi.org/10.1016/j.neuropharm.2018.01.036CrossRefGoogle Scholar
Padgett, CL, Hanek, AP, Lester, HA, Dougherty, DA, and Lummis, SCRR (2007) Unnatural amino acid mutagenesis of the GABAA receptor binding site residues reveals a novel cation- interaction between GABA and beta 2Tyr97. The Journal of Neuroscience 27(4), 886–892. https://doi.org/10.1523/JNEUROSCI.4791-06.2007CrossRefGoogle ScholarPubMed
Pálvölgyi, A, Móricz, K, Pataki, Á, Mihalik, B, Gigler, G, Megyeri, K, Udvari, S, Gacsályi, I, and Antoni, FA (2018) Loop F of the GABAA receptor alpha subunit governs GABA potency. Neuropharmacology 128, 408–415. https://doi.org/10.1016/j.neuropharm.2017.10.042CrossRefGoogle Scholar
Patel, B, Mortensen, M, and Smart, TG (2014) Stoichiometry of δ subunit containing GABAA receptors. British Journal of Pharmacology 171(4), 985–994. https://doi.org/10.1111/bph.12514CrossRefGoogle Scholar
Petrini, EM, Ravasenga, T, Hausrat, TJ, Iurilli, G, Olcese, U, Racine, V, Sibarita, JB, Jacob, TC, Moss, SJ, Benfenati, F, Medini, P, Kneussel, M, and Barberis, A (2014) Synaptic recruitment of gephyrin regulates surface GABAA receptor dynamics for the expression of inhibitory LTP. Nat Commun 5, 3921. https://doi.org/10.1038/ncomms4921CrossRefGoogle ScholarPubMed
Phulera, S, Zhu, H, Yu, J, Claxton, DP, Yoder, N, Yoshioka, C, and Gouaux, E (2018) Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA. ELife 7, 1–21. https://doi.org/10.7554/eLife.39383CrossRefGoogle ScholarPubMed
Pierce, SR, Germann, AL, Evers, AS, Steinbach, JH, and Akk, G (2020) Reduced activation of the synaptic-type GABAA receptor following prolonged exposure to low concentrations of agonists: relationship between tonic activity and desensitization. Molecular Pharmacology 98(6), 762–769. https://doi.org/10.1124/molpharm.120.000088CrossRefGoogle ScholarPubMed
Pierce, SR, Germann, AL, Steinbach, JH, and Akk, G (2022) The Sulfated steroids pregnenolone sulfate and dehydroepiandrosterone sulfate inhibit the α1β3γ2L GABAA receptor by stabilizing a novel nonconducting state. Molecular Pharmacology 101(2), 68–77. https://doi.org/10.1124/MOLPHARM.121.000385CrossRefGoogle ScholarPubMed
Pizzarelli, R, Griguoli, M, Zacchi, P, Petrini, EM, Barberis, A, Cattaneo, A, and Cherubini, E (2020) Tuning GABAergic inhibition: gephyrin molecular organization and functions. Neuroscience 439, 125–136. https://doi.org/10.1016/j.neuroscience.2019.07.036CrossRefGoogle Scholar
Puthenkalam, R, Hieckel, M, Simeone, X, Suwattanasophon, C, Feldbauer, Rv, Ecker, GF, and Ernst, M (2016) Structural studies of GABAA receptor binding sites: which experimental structure tells us what? Frontiers in Molecular Neuroscience 9 6, 1–20. https://doi.org/10.3389/fnmol.2016.00044CrossRefGoogle Scholar
Pytel, M, Mercik, K, and Mozrzymas, JW (2003) Resolving the ionotropic receptor kinetics and modulation in the time scale of synaptic transmission. Cellular and Molecular Biology Letters 8, 231–241.Google ScholarPubMed
Riva, I, Eibl, C, Volkmer, R, Carbone, AL, and Plested, AJ (2017) Control of AMPA receptor activity by the extracellular loops of auxiliary proteins. Elife 6. https://doi.org/10.7554/eLife.28680CrossRefGoogle ScholarPubMed
Rivera, C, Voipio, J, and Kaila, K (2005) Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII. The Journal of Physiology 562(Pt 1), 27–36. https://doi.org/10.1113/JPHYSIOL.2004.077495CrossRefGoogle ScholarPubMed
Rosen, A, Bali, M, Horenstein, J, and Akabas, MH (2007) Channel opening by anesthetics and GABA induces similar changes in the GABAA receptor M2 segment. Biophysical Journal 92(9), 3130–3139. https://doi.org/10.1529/biophysj.106.094490CrossRefGoogle ScholarPubMed
Rudolph, U, and Möhler, H (2006) GABA-based therapeutic approaches: GABAA receptor subtype functions. Current Opinion in Pharmacology 6(1), 18–23. https://doi.org/10.1016/j.coph.2005.10.003CrossRefGoogle ScholarPubMed
Sachidanandan, D, and Bera, AK (2015) Inhibition of the GABAA receptor by sulfated neurosteroids: a mechanistic comparison study between pregnenolone sulfate and dehydroepiandrosterone sulfate. Journal of Molecular Neuroscience 56(4), 868–877. https://doi.org/10.1007/s12031-015-0527-4CrossRefGoogle ScholarPubMed
Saliba, RS, Kretschmannova, K, and Moss, SJ (2012) Activity-dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current. EMBO Journal 31(13), 2937–2951. https://doi.org/10.1038/emboj.2012.109CrossRefGoogle ScholarPubMed
Sallard, E, Letourneur, D, and Legendre, P (2021) Electrophysiology of ionotropic GABA receptors. Cellular and Molecular Life Sciences 78(13), 5341–5370. https://doi.org/10.1007/s00018-021-03846-2CrossRefGoogle ScholarPubMed
Sauguet, L, Shahsavar, A, Poitevin, F, Huon, C, Menny, A, Nemecz, A, Haouz, A, Changeux, J-P, Corringer, P-J, and Delarue, M (2014) Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation. Proceedings of the National Academy of Sciences 111(3), 966–971. https://doi.org/10.1073/pnas.1314997111CrossRefGoogle ScholarPubMed
Scheller, M, and Forman, SA (2002) Coupled and Uncoupled Gating and Desensitization Effects by Pore Domain Mutations in GABA A Receptors.CrossRefGoogle Scholar
Scimemi, A, and Beato, M (2009) Determining the neurotransmitter concentration profile at active synapses. Molecular Neurobiology 40(3), 289–306. https://doi.org/10.1007/S12035-009-8087-7CrossRefGoogle ScholarPubMed
Scott, S, and Aricescu, AR (2019) A structural perspective on GABA A receptor pharmacology. Current Opinion in Structural Biology 54, 189–197. https://doi.org/10.1016/j.sbi.2019.03.023CrossRefGoogle Scholar
Sedelnikova, A, Erkkila, BE, Harris, H, Zakharkin, SO, and Weiss, DS (2006) Stoichiometry of a pore mutation that abolishes picrotoxin-mediated antagonism of the GABAA receptor. The Journal of Physiology 577(Pt 2), 569–577. https://doi.org/10.1113/JPHYSIOL.2006.120287CrossRefGoogle ScholarPubMed
Seljeset, S, Bright, DP, Thomas, P, and Smart, TG (2018) Probing GABAAreceptors with inhibitory neurosteroids. Neuropharmacology 136, 23–36. https://doi.org/10.1016/j.neuropharm.2018.02.008CrossRefGoogle Scholar
Senju, Y, and Tsai, FC (2022) A biophysical perspective of the regulatory mechanisms of ezrin/radixin/moesin proteins. Biophysical Reviews 14(1), 199–208. https://doi.org/10.1007/s12551-021-00928-0CrossRefGoogle ScholarPubMed
Sente, A, Desai, R, Naydenova, K, Malinauskas, T, Jounaidi, Y, Miehling, J, Zhou, X, Masiulis, S, Hardwick, SW, Chirgadze, DY, Miller, KW, and Aricescu, AR (2022) Differential assembly diversifies GABAA receptor structures and signalling. Nature 604(7904), 190–194. https://doi.org/10.1038/s41586-022-04517-3CrossRefGoogle ScholarPubMed
Sexton, CA, Penzinger, R, Mortensen, M, Bright, DP, and Smart, TG (2021) Structural determinants and regulation of spontaneous activity in GABAA receptors. Nature Communications 12(1), 5457. https://doi.org/10.1038/s41467-021-25633-0CrossRefGoogle Scholar
Sharkey, LM, and Czajkowski, C (2008) Individually monitoring ligand-induced changes in the structure of the GABA A receptor at benzodiazepine binding site and non – binding-site interfaces. Drugs 74(1), 203–212. https://doi.org/10.1124/mol.108.044891.bindingGoogle ScholarPubMed
Shin, DJ, Germann, AL, Covey, DF, Steinbach, JH, and Akk, G (2019) Analysis of GABAA receptor activation by combinations of agonists acting at the same or distinct binding sites. Molecular Pharmacology 95(1), 70–81. https://doi.org/10.1124/MOL.118.113464CrossRefGoogle ScholarPubMed
Shin, DJ, Germann, AL, Johnson, AD, Forman, SA, Steinbach, JH, and Akk, G (2018) Propofol is an allosteric agonist with multiple binding sites on concatemeric ternary GABA A receptors. Molecular Pharmacology 93(2), 178–189. https://doi.org/10.1124/mol.117.110403CrossRefGoogle Scholar
Sieghart, W, and Savić, MM (2018) International union of basic and clinical pharmacology. CVI: GABAA receptor subtype- and function-selective ligands: key issues in translation to humans. Pharmacological Reviews 70(4), 836–878. https://doi.org/10.1124/pr.117.014449CrossRefGoogle ScholarPubMed
Siegwart, R, Jurd, R, and Rudolph, U (2002) Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors. Journal of Neurochemistry 80(1), 140–148. https://doi.org/10.1046/J.0022-3042.2001.00682.XCrossRefGoogle Scholar
Siegwart, R, Krähenbühl, K, Lambert, S, and Rudolph, U (2003) Mutational analysis of molecular requirements for the actions of general anaesthetics at the gamma-aminobutyric acidA receptor subtype alpha1beta2gamma2. BMC Pharmacology 3. https://doi.org/10.1186/1471-2210-3-13CrossRefGoogle ScholarPubMed
Sigel, E, Baur, R, Kellenberger, S, Malherbel, P, Malherbe, P, and Malherbel, P (1992) Point mutations affecting antagonist affinity and agonist dependent gating of GABAA receptor channels. The EMBO Journal 11(6), 2017–2023. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=556666&tool=pmcentrez&rendertype=abstractCrossRefGoogle ScholarPubMed
Sigel, E, and Ernst, M (2018) The benzodiazepine binding sites of GABAA receptors. Trends in Pharmacological Sciences 39(7), 659–671. https://doi.org/10.1016/j.tips.2018.03.006CrossRefGoogle Scholar
Steinbach, JH, and Akk, G (2019) Applying the Monod-Wyman-Changeux allosteric activation model to pseudo–steady-state responses from GABAA receptors. Molecular Pharmacology 95(1), 106–119. https://doi.org/10.1124/mol.118.113787CrossRefGoogle Scholar
Stewart, D, Desai, R, Cheng, Q, Liu, A, and Forman, SA (2008) Tryptophan mutations at Azi-etomidate photo-incorporation sites on α1 or β2 subunits enhance gabaa receptor gating and reduce etomidate modulation. Molecular Pharmacology 74(6), 1687–1695. https://doi.org/10.1124/MOL.108.050500CrossRefGoogle ScholarPubMed
Stewart, DS, Hotta, M, Desai, R, and Forman, SA (2013a) State-dependent etomidate occupancy of its allosteric agonist sites measured in a cysteine-substituted GABAA receptor. Molecular Pharmacology 83(6), 1200–1208. https://doi.org/10.1124/mol.112.084558CrossRefGoogle Scholar
Stewart, DS, Hotta, M, Li, GD, Desai, R, Chiara, DC, Olsen, RW, and Forman, SA (2013b) Cysteine substitutions define etomidate binding and gating linkages in the α-M1 domain of γ-aminobutyric acid type A (GABAA) receptors. The Journal of Biological Chemistry 288(42), 30373–30386. https://doi.org/10.1074/JBC.M113.494583CrossRefGoogle ScholarPubMed
Stewart, DS, Pierce, DW, Hotta, M, Stern, AT, and Forman, SA (2014) Mutations at beta N265 in c-aminobutyric acid type a receptors alter both binding affinity and efficacy of potent anesthetics. PLoS ONE 9(10), 1–12. https://doi.org/10.1371/journal.pone.0111470CrossRefGoogle Scholar
Sugasawa, Y, Bracamontes, JR, Krishnan, K, Covey, DF, Reichert, DE, Akk, G, Chen, Q, Tang, P, Evers, AS, and Cheng, WWL (2019) The molecular determinants of neurosteroid binding in the GABA(A) receptor. The Journal of Steroid Biochemistry and Molecular Biology 192, 105383. https://doi.org/10.1016/J.JSBMB.2019.105383CrossRefGoogle ScholarPubMed
Sugasawa, Y, Cheng, WW, Bracamontes, JR, Chen, Z-W, Wang, L, Germann, AL, Pierce, SR, Senneff, TC, Krishnan, K, Reichert, DE, Covey, DF, Akk, G, and Evers, AS (2020) Site-specific effects of neurosteroids on GABAA receptor activation and desensitization. ELife 9, 1–32. https://doi.org/10.7554/eLife.55331CrossRefGoogle ScholarPubMed
Sun, C, Zhu, H, Clark, S, and Gouaux, E (2023) Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology. Nature 622(7981), 195–201. https://doi.org/10.1038/s41586-023-06556-wCrossRefGoogle ScholarPubMed
Szabo, A, Nourmahnad, A, Halpin, E, and Forman, SA (2019) Monod-Wyman-changeux allosteric shift analysis in mutant α1β3γ2L GABAA receptors indicates selectivity and cross-talk among intersubunit transmembrane anesthetic sites. Molecular Pharmacology 95(4), mol.118.115048. https://doi.org/10.1124/mol.118.115048CrossRefGoogle Scholar
Szczot, M, Kisiel, M, Czyzewska, MM, and Mozrzymas, JW (2014) α1F64 Residue at GABA(A) receptor binding site is involved in gating by influencing the receptor flipping transitions. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 34(9), 3193–3209. https://doi.org/10.1523/JNEUROSCI.2533-13.2014CrossRefGoogle ScholarPubMed
Tan, KR, Rudolph, U, and Lüscher, C (2011) Hooked on benzodiazepines: GABAAreceptor subtypes and addiction. Trends in Neurosciences 34(4), 188–197. https://doi.org/10.1016/j.tins.2011.01.004CrossRefGoogle Scholar
Tateiwa, H, Chintala, SM, Chen, Z, Wang, L, Amtashar, F, Bracamontes, J, Germann, AL, Pierce, SR, Covey, DF, Akk, G, and Evers, AS (2023) The mechanism of enantioselective neurosteroid actions on GABAA receptors. Biomolecules 13(2) https://doi.org/10.3390/BIOM13020341CrossRefGoogle Scholar
Terejko, K, Kaczor, PT, Michałowski, MA, Dąbrowska, A, and Mozrzymas, JW (2020) The C loop at the orthosteric binding site is critically involved in GABAA receptor gating. Neuropharmacology 166(11), 107903. https://doi.org/10.1016/j.neuropharm.2019.107903CrossRefGoogle Scholar
Terejko, K, Michałowski, MA, Dominik, A, Andrzejczak, A, and Mozrzymas, JW (2021a) Interaction between GABAA receptor α1 and β2 subunits at the N-terminal peripheral regions is crucial for receptor binding and gating. Biochemical Pharmacology 183(9), 114338. https://doi.org/10.1016/j.bcp.2020.114338CrossRefGoogle ScholarPubMed
Terejko, K, Michałowski, MA, Iżykowska, I, Dominik, A, Brzóstowicz, A, and Mozrzymas, JW (2021b) Mutations at the M2 and M3 transmembrane helices of the GABA A Rs α 1 and β 2 subunits affect primarily late gating transitions including opening/closing and desensitization. ACS Chemical Neuroscience 12(13), 2421–2436. https://doi.org/10.1021/acschemneuro.1c00151CrossRefGoogle Scholar
Tierney, ML, Birnir, B, Pillai, NP, Clements, JD, Howitt, SM, Cox, GB, and Gage, PW (1996) Effects of mutating leucine to threonine in the M2 segment of α1 and β1 subunits of GABAA α1β1 receptors. Journal Membrane Biology 154 (1), 11–21.CrossRefGoogle Scholar
Topf, N, Jenkins, A, Baron, N, and Harrison, NL (2003) Effects of Isoflurane on-aminobutyric acid type A receptors activated by full and partial agonists. Anesthesiology 98, 306–311.CrossRefGoogle ScholarPubMed
Toyoda, H, Saito, M, Sato, H, Tanaka, T, Ogawa, T, Yatani, H, Kawano, T, Kanematsu, T, Hirata, M, and Kang, Y (2015) Enhanced desensitization followed by unusual resensitization in GABAA receptors in phospholipase C-related catalytically inactive protein-1/2 double-knockout mice. Pflugers Archiv: European Journal of Physiology 467(2), 267–284. https://doi.org/10.1007/S00424-014-1511-5CrossRefGoogle ScholarPubMed
Tran, PN, Laha, KT, and Wagner, DA (2011) A tight coupling between β 2Y97 and β 2F200 of the GABA A receptor mediates GABA binding. Journal of Neurochemistry 119(2), 283–293. https://doi.org/10.1111/j.1471-4159.2011.07409.xCrossRefGoogle ScholarPubMed
Uchański, T, Masiulis, S, Fischer, B, Kalichuk, V, López-Sánchez, U, Zarkadas, E, Weckener, M, Sente, A, Ward, P, Wohlkönig, A, Zögg, T, Remaut, H, Naismith, JH, Nury, H, Vranken, W, Aricescu, AR, Pardon, E, and Steyaert, J (2021) Megabodies expand the nanobody toolkit for protein structure determination by single-particle cryo-EM. Nature Methods 18(1), 60–68. https://doi.org/10.1038/s41592-020-01001-6CrossRefGoogle ScholarPubMed
Ueno, S, Lin, A, Nikolaeva, N, Trudell, JR, John Mihic, S, Adron Harris, R, and Harrison, NL (2000) Tryptophan scanning mutagenesis in TM2 of the GABA A receptor a subunit: e€ects on channel gating and regulation by ethanol 1,6. British Journal of Pharmacology 131, 296–302.CrossRefGoogle Scholar
Unwin, N (2005) Refined structure of the nicotinic acetylcholine receptor at 4 A resolution. Journal of Molecular Biology 346(4), 967–989. https://doi.org/10.1016/j.jmb.2004.12.031CrossRefGoogle Scholar
Venkatachalan, SP, and Czajkowski, C (2008) A conserved salt bridge critical for GABA(A) receptor function and loop C dynamics. Proceedings of the National Academy of Sciences of the United States of America 105(36), 13604–13609. https://doi.org/10.1073/pnas.0801854105CrossRefGoogle ScholarPubMed
Venkatachalan, SP, and Czajkowski, C (2012) Structural link between gamma-aminobutyric acid type A (GABAA) receptor agonist binding site and inner beta-sheet governs channel activation and allosteric drug modulation. Journal of Biological Chemistry 287(9), 6714–6724. https://doi.org/10.1074/jbc.M111.316836CrossRefGoogle ScholarPubMed
Wagner, DA, Czajkowski, C, and Jones, MV (2004) An arginine involved in GABA binding and unbinding but not gating of the GABA(A) receptor. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 24(11), 2733–2741. https://doi.org/10.1523/JNEUROSCI.4316-03.2004CrossRefGoogle Scholar
Wagner, DA, Goldschen-Ohm, MP, Hales, TG, and Jones, MV (2005) Kinetics and spontaneous open probability conferred by the epsilon subunit of the GABAA receptor. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 25(45), 10462–10468. https://doi.org/10.1523/JNEUROSCI.1658-05.2005CrossRefGoogle ScholarPubMed
Walker, MC, and Semyanov, A (2008) Regulation of excitability by extrasynaptic GABA(A) receptors. Results and Problems in Cell Differentiation 44, 29–48. https://doi.org/10.1007/400_2007_030CrossRefGoogle ScholarPubMed
Wang, Q, Pless, SA, and Lynch, JW (2010) Ligand- and subunit-specific conformational changes in the ligand-binding domain and the TM2-TM3 linker of {alpha}1 {beta}2 {gamma}2 GABAA receptors. The Journal of Biological Chemistry 285(51), 40373–40386. https://doi.org/10.1074/JBC.M110.161513CrossRefGoogle ScholarPubMed
Wermuth, CG, and Bizière, K (1986) Pyridazinyl-GABA derivatives: a new class of synthetic GABAA antagonists. Trends in Pharmacological Sciences 7(C), 421–424. https://doi.org/10.1016/0165-6147(86)90408-6CrossRefGoogle Scholar
Westh-Hansen, SE, Rasmussen, PB, Hastrup, S, Nabekura, J, Noguchi, K, Akaike, N, Witt, MR and Nielsen, M (1997) Decreased agonist sensitivity of human GABAA receptors by an amino acid variant, isoleucine to valine, in the α1 subunit. European Journal of Pharmacology 329(2–3), 253–257. https://doi.org/10.1016/S0014-2999(97)89186-8CrossRefGoogle Scholar
Westh-Hansen, SE, Witt, MR, Dekermendjian, K, Liljefors, T, Rasmussen, PB, and Nielsen, M (1999) Arginine residue 120 of the human GABAA receptor alpha 1, subunit is essential for GABA binding and chloride ion current gating. Neuroreport 10(11), 2417–2421. https://doi.org/10.1097/00001756-199908020-00036CrossRefGoogle ScholarPubMed
Wiera, G, Brzdąk, P, Lech, AM, Lebida, K, Jabłońska, J, Gmerek, P, and Mozrzymas, JW (2022) Integrins bidirectionally regulate the efficacy of inhibitory synaptic transmission and control GABAergic plasticity. Journal of Neuroscience 42(30), 5830–5842. https://doi.org/10.1523/jneurosci.1458-21.2022CrossRefGoogle ScholarPubMed
Wiera, G, Lebida, K, Lech, AM, Brzdąk, P, Van Hove, I, De Groef, L, Moons, L, Petrini, EM, Barberis, A, and Mozrzymas, JW (2021) Long-term plasticity of inhibitory synapses in the hippocampus and spatial learning depends on matrix metalloproteinase 3. Cellular and Molecular Life Sciences 78(5), 2279–2298. https://doi.org/10.1007/s00018-020-03640-6CrossRefGoogle ScholarPubMed
Wilkins, ME, Hosie, AM, and Smart, TG (2002) Identification of a beta subunit TM2 residue mediating proton modulation of GABA type A receptors. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 22(13), 5328–5333. https://doi.org/10.1523/JNEUROSCI.22-13-05328.2002CrossRefGoogle ScholarPubMed
Wilkins, ME, Hosie, AM, and Smart, TG (2005) Proton modulation of recombinant GABAA receptors: influence of GABA concentration and the β subunit TM2-TM3 domain. Journal of Physiology 567(2), 365–377. https://doi.org/10.1113/jphysiol.2005.088823CrossRefGoogle ScholarPubMed
Wooltorton, JRA, Mcdonald, BJ, Moss, SJ, and Smart, TG (1997) Identification of a Zn2+ binding site on the murine GABAA receptor complex: dependence on the second transmembrane domain of/subunits. Journal of Physiology 505, 633–640.CrossRefGoogle ScholarPubMed
Wu, K, Castellano, D, Tian, Q, and Lu, W (2021a) Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes. Cell Reports 37(6), 109960. https://doi.org/10.1016/j.celrep.2021.109960CrossRefGoogle ScholarPubMed
Wu, K, Han, W, and Lu, W (2022a) Sleep and wake cycles dynamically modulate hippocampal inhibitory synaptic plasticity. PLoS Biology 20(11) https://doi.org/10.1371/JOURNAL.PBIO.3001812CrossRefGoogle ScholarPubMed
Wu, K, Han, W, Tian, Q, Li, Y, and Lu, W (2021b) Activity- and sleep-dependent regulation of tonic inhibition by Shisa7. Cell Reports 34(12), 108899. https://doi.org/10.1016/j.celrep.2021.108899CrossRefGoogle ScholarPubMed
Wu, K, Shepard, RD, Castellano, D, Han, W, Tian, Q, Dong, L, and Lu, W (2022b) Shisa7 phosphorylation regulates GABAergic transmission and neurodevelopmental behaviors. Neuropsychopharmacology 2022, 1–11. https://doi.org/10.1038/s41386-022-01334-0Google Scholar
Wyroślak, M, Dobrzański, G, and Mozrzymas, JW (2023) Bidirectional plasticity of GABAergic tonic inhibition in hippocampal somatostatin- and parvalbumin-containing interneurons. Frontiers in Cellular Neuroscience 17, 1193383. https://doi.org/10.3389/fncel.2023.1193383CrossRefGoogle ScholarPubMed
Wyroślak, M, Lebida, K, and Mozrzymas, JW (2021) Induction of inhibitory synaptic plasticity enhances tonic current by increasing the content of α5-subunit containing GABA(A) receptors in hippocampal pyramidal neurons. Neuroscience 467, 39–46. https://doi.org/10.1016/j.neuroscience.2021.05.020CrossRefGoogle ScholarPubMed
Xie, HB, Wang, J, Sha, Y, and Cheng, MS (2013) Molecular dynamics investigation of Cl− transport through the closed and open states of the 2α12β2γ2 GABAA receptor. Biophysical Chemistry 180 –181, 1–9. https://doi.org/10.1016/J.BPC.2013.05.004CrossRefGoogle Scholar
Yip, GMS, Chen, Z-W, Edge, CJ, Smith, EH, Dickinson, R, Hohenester, E, Townsend, RR, Fuchs, K, Sieghart, W, Evers, AS, and Franks, NP (2013) A propofol binding site on mammalian GABAA receptors identified by photolabeling. Nature Chemical Biology 9(11), 715–720. https://doi.org/10.1038/nchembio.1340CrossRefGoogle ScholarPubMed
Yu, J, Zhu, H, Lape, R, Greiner, T, Du, J, Lü, W, Sivilotti, L, and Gouaux, E (2021) Mechanism of gating and partial agonist action in the glycine receptor. Cell 184(4), 957–968.e21. https://doi.org/10.1016/j.cell.2021.01.026CrossRefGoogle ScholarPubMed
Zacchi, P, Antonelli, R, and Cherubini, E (2014) Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses. Frontiers in Cellular Neuroscience 8, 103. https://doi.org/10.3389/fncel.2014.00103CrossRefGoogle ScholarPubMed
Zarkadas, E, Pebay-Peyroula, E, Thompson, MJ, Schoehn, G, Uchański, T, Steyaert, J, Chipot, C, Dehez, F, Baenziger, JE, and Nury, H (2022) Conformational transitions and ligand-binding to a muscle-type nicotinic acetylcholine receptor. Neuron 110(8), 1–13. https://doi.org/10.1016/j.neuron.2022.01.013CrossRefGoogle ScholarPubMed
Zhu, S, Noviello, CM, Teng, J, Walsh, RM, Kim, JJ, and Hibbs, RE (2018) Structure of a human synaptic GABAA receptor. Nature 1, https://doi.org/10.1038/s41586-018-0255-3Google Scholar
Zhu, S, Sridhar, A, Teng, J, Howard, RJ, Lindahl, E, and Hibbs, RE (2022) Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities. Nature Communications 2022 13:1 13(1), 1–13. https://doi.org/10.1038/s41467-022-32212-4Google ScholarPubMed
Ziemba, AM, Szabo, A, Pierce, DW, Haburcak, M, Stern, AT, Nourmahnad, A, Halpin, ES, and Forman, SA (2018) Alphaxalone binds in inner transmembrane β+-α- interfaces of α1β3γ2 γ-aminobutyric acid type A receptors. Anesthesiology 128(2), 338–351. https://doi.org/10.1097/ALN.0000000000001978CrossRefGoogle ScholarPubMed