Molecular mechanisms of metabotropic GABAB receptor function

Shaye, Hamidreza; Stauch, Benjamin; Gati, Cornelius; Cherezov, Vadim

doi:10.1126/sciadv.abg3362

Molecular mechanisms of metabotropic GABA_B receptor function

Journal Article · Fri May 28 00:00:00 EDT 2021 · Science Advances

DOI:https://doi.org/10.1126/sciadv.abg3362· OSTI ID:1808718

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Univ. of Southern California, Los Angeles, CA (United States)
Univ. of Southern California, Los Angeles, CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABA_B) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABA_B. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABA_B receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institute of General Medical Sciences

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1808718

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 22 Vol. 7; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

References (117)

GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy: GABBR2 Mutations Determine RTT- or EE-Phenotypes Yoo, Yongjin; Jung, Jane; Lee, Yoo-Na Annals of Neurology, Vol. 82, Issue 3 https://doi.org/10.1002/ana.25032	journal	September 2017
A novel mutation in the transmembrane 6 domain of GABBR2 leads to a Rett-like phenotype: Letter to the Editor Vuillaume, Marie-Laure; Jeanne, Médéric; Xue, Li Annals of Neurology, Vol. 83, Issue 2 https://doi.org/10.1002/ana.25155	journal	February 2018
Selective effects of (?)-baclofen on spinal synaptic transmission in the cat Curtis, D. R.; Lodge, D.; Bornstein, J. C. Experimental Brain Research, Vol. 42, Issue 2 https://doi.org/10.1007/BF00236902	journal	April 1981
The action of γ-Aminobutyric acid on cortical neurones Krnjević, K.; Schwartz, Susan Experimental Brain Research, Vol. 3, Issue 4 https://doi.org/10.1007/BF00237558	journal	May 1967
Some approaches to the directed search for new drugs based on nicotinic acid Kopelevich, V. M.; Gunar, V. I. Pharmaceutical Chemistry Journal, Vol. 33, Issue 4 https://doi.org/10.1007/BF02509934	journal	April 1999
Effect of tramiprosate in patients with mild-to-moderate alzheimer’s disease: Exploratory analyses of the MRI sub-group of the alphase study Gauthier, S.; Aisen, P. S.; Ferris, S. H. The Journal of Nutrition, Health and Aging, Vol. 13, Issue 6 https://doi.org/10.1007/s12603-009-0106-x	journal	June 2009
A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes Mignot, Emmanuel J. M. Neurotherapeutics, Vol. 9, Issue 4 https://doi.org/10.1007/s13311-012-0150-9	journal	October 2012
Phaclofen: a peripheral and central baclofen antagonist Kerr, David I. B.; Ong, Jennifer; Prager, Rolf H. Brain Research, Vol. 405, Issue 1 https://doi.org/10.1016/0006-8993(87)90999-1	journal	March 1987
The (S)-enantiomer of 2-hydroxysaclofen is the active GABAB receptor antagonist in central and peripheral preparations Kerr, David I. B.; Ong, Jennifer; Doolette, David J. European Journal of Pharmacology, Vol. 287, Issue 2 https://doi.org/10.1016/0014-2999(95)00641-9	journal	December 1995
GABAB receptor antagonism by resolved (R)-saclofen in the guinea-pig ileum Kerr, David I. B.; Ong, Jennifer; Vaccher, Claude European Journal of Pharmacology, Vol. 308, Issue 3 https://doi.org/10.1016/0014-2999(96)00334-2	journal	July 1996
Analysis of membrane and surface protein sequences with the hydrophobic moment plot Eisenberg, D.; Schwarz, E.; Komaromy, M. Journal of Molecular Biology, Vol. 179, Issue 1 https://doi.org/10.1016/0022-2836(84)90309-7	journal	October 1984
Regulation by divalent cations of 3H-baclofen binding to GABAB sites in rat cerebellar membranes Kato, Koki; Goto, Masayoshi; Fukuda, Hideomi Life Sciences, Vol. 32, Issue 8 https://doi.org/10.1016/0024-3205(83)90225-4	journal	February 1983
CGP 36216 is a selective antagonist at GABAB presynaptic receptors in rat brain Ong, Jennifer; Bexis, Sotiria; Marino, Victor European Journal of Pharmacology, Vol. 415, Issue 2-3 https://doi.org/10.1016/S0014-2999(01)00842-1	journal	March 2001
Unsaturated phosphinic analogues of γ-aminobutyric acid as GABAC receptor antagonists Chebib, Mary; Vandenberg, Robert J.; Froestl, Wolfgang European Journal of Pharmacology, Vol. 329, Issue 2-3 https://doi.org/10.1016/S0014-2999(97)89183-2	journal	June 1997
Free γ-Aminobutyric acid in Brain Awapara, Jorge; Landua, Alton J.; Fuerst, Robert Journal of Biological Chemistry, Vol. 187, Issue 1 https://doi.org/10.1016/S0021-9258(19)50926-7	journal	November 1950
γ-Aminobutyric acid in Brain: its Formation from Glutamic acid Roberts, Eugene; Frankel, Sam Journal of Biological Chemistry, Vol. 187, Issue 1 https://doi.org/10.1016/S0021-9258(19)50929-2	journal	November 1950
Calcium sensing properties of the GABAB receptor Wise, A. Neuropharmacology, Vol. 38, Issue 11 https://doi.org/10.1016/S0028-3908(99)00119-7	journal	November 1999
The effects of GABAB agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat Patel, Sadhana; Naeem, Sami; Kesingland, Adam Pain, Vol. 90, Issue 3 https://doi.org/10.1016/S0304-3959(00)00404-8	journal	January 2001
GABAB receptor agonists for the treatment of drug addiction: a review of recent findings Cousins, Michael S.; Roberts, David C. S.; Wit, Harriet de Drug and Alcohol Dependence, Vol. 65, Issue 3 https://doi.org/10.1016/S0376-8716(01)00163-6	journal	February 2002
Epilepsy, Hyperalgesia, Impaired Memory, and Loss of Pre- and Postsynaptic GABAB Responses in Mice Lacking GABAB(1) Schuler, Valérie; Lüscher, Christian; Blanchet, Christophe Neuron, Vol. 31, Issue 1 https://doi.org/10.1016/S0896-6273(01)00345-2	journal	July 2001
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan, Fadi F.; Myers, Candace T.; Cossette, Patrick The American Journal of Human Genetics, Vol. 101, Issue 5 https://doi.org/10.1016/j.ajhg.2017.09.008	journal	November 2017
A 10-year meta-analysis of membrane protein structural biology: Detergents, membrane mimetics, and structure determination techniques Choy, Brendon C.; Cater, Rosemary J.; Mancia, Filippo Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1863, Issue 3 https://doi.org/10.1016/j.bbamem.2020.183533	journal	March 2021
SGS742: the first GABAB receptor antagonist in clinical trials Froestl, Wolfgang; Gallagher, Michela; Jenkins, Helen Biochemical Pharmacology, Vol. 68, Issue 8 https://doi.org/10.1016/j.bcp.2004.07.030	journal	October 2004
Ethers of 3-hydroxyphenylacetic acid as selective gamma-hydroxybutyric acid receptor ligands Chen, Weibin; Wu, Huifang; Hernandez, R. Jason Bioorganic & Medicinal Chemistry Letters, Vol. 15, Issue 13 https://doi.org/10.1016/j.bmcl.2005.05.011	journal	July 2005
FRET-Based Sensors Unravel Activation and Allosteric Modulation of the GABA B Receptor Lecat-Guillet, Nathalie; Monnier, Carine; Rovira, Xavier Cell Chemical Biology, Vol. 24, Issue 3 https://doi.org/10.1016/j.chembiol.2017.02.011	journal	March 2017
Structural Basis for Activation of the Heterodimeric GABAB Receptor Kim, Yoojoong; Jeong, Eunyoung; Jeong, Ji-Hong Journal of Molecular Biology, Vol. 432, Issue 22 https://doi.org/10.1016/j.jmb.2020.09.023	journal	November 2020
Mechanism of Assembly and Cooperativity of Homomeric and Heteromeric Metabotropic Glutamate Receptors Levitz, Joshua; Habrian, Chris; Bharill, Shashank Neuron, Vol. 92, Issue 1 https://doi.org/10.1016/j.neuron.2016.08.036	journal	October 2016
γ-Hydroxybutyric acid (GHB) and γ-aminobutyric acidB receptor (GABABR) binding sites are distinctive from one another: molecular evidence Wu, Ying; Ali, Saima; Ahmadian, Gholamreza Neuropharmacology, Vol. 47, Issue 8 https://doi.org/10.1016/j.neuropharm.2004.08.019	journal	December 2004
GABAB receptors as a therapeutic strategy in substance use disorders: Focus on positive allosteric modulators Filip, Małgorzata; Frankowska, Małgorzata; Sadakierska-Chudy, Anna Neuropharmacology, Vol. 88 https://doi.org/10.1016/j.neuropharm.2014.06.016	journal	January 2015
GABAB receptors and pain Malcangio, Marzia Neuropharmacology, Vol. 136 https://doi.org/10.1016/j.neuropharm.2017.05.012	journal	July 2018
GABAA receptor: Positive and negative allosteric modulators Olsen, Richard W. Neuropharmacology, Vol. 136 https://doi.org/10.1016/j.neuropharm.2018.01.036	journal	July 2018
Behavioral analyses of GHB: Receptor mechanisms Carter, Lawrence P.; Koek, Wouter; France, Charles P. Pharmacology & Therapeutics, Vol. 121, Issue 1 https://doi.org/10.1016/j.pharmthera.2008.10.003	journal	January 2009
Beyond structure: emerging approaches to study GPCR dynamics Gusach, Anastasiia; Maslov, Ivan; Luginina, Aleksandra Current Opinion in Structural Biology, Vol. 63 https://doi.org/10.1016/j.sbi.2020.03.004	journal	August 2020
A Bright Future for Serial Femtosecond Crystallography with XFELs Johansson, Linda C.; Stauch, Benjamin; Ishchenko, Andrii Trends in Biochemical Sciences, Vol. 42, Issue 9 https://doi.org/10.1016/j.tibs.2017.06.007	journal	September 2017
Structural and Biophysical Mechanisms of Class C G Protein-Coupled Receptor Function Ellaithy, Amr; Gonzalez-Maeso, Javier; Logothetis, Diomedes A. Trends in Biochemical Sciences, Vol. 45, Issue 12 https://doi.org/10.1016/j.tibs.2020.07.008	journal	December 2020
Generic GPCR residue numbers – aligning topology maps while minding the gaps Isberg, Vignir; de Graaf, Chris; Bortolato, Andrea Trends in Pharmacological Sciences, Vol. 36, Issue 1 https://doi.org/10.1016/j.tips.2014.11.001	journal	January 2015
The Benzodiazepine Binding Sites of GABAA Receptors Sigel, Erwin; Ernst, Margot Trends in Pharmacological Sciences, Vol. 39, Issue 7 https://doi.org/10.1016/j.tips.2018.03.006	journal	July 2018
Structure–Activity Studies Reveal the Molecular Basis for GABA _B -Receptor Mediated Inhibition of High Voltage-Activated Calcium Channels by α-Conotoxin Vc1.1 Sadeghi, Mahsa; Carstens, Bodil B.; Callaghan, Brid P. ACS Chemical Biology, Vol. 13, Issue 6 https://doi.org/10.1021/acschembio.8b00190	journal	May 2018
Classics in Chemical Neuroscience: Baclofen Kent, Caitlin N.; Park, Charlotte; Lindsley, Craig W. ACS Chemical Neuroscience, Vol. 11, Issue 12 https://doi.org/10.1021/acschemneuro.0c00254	journal	May 2020
Phosphinic Acid Analogs of GABA. 1. New Potent and Selective GABAB Agonists Froestl, Wolfgang; Mickel, Stuart J.; Hall, Roger G. Journal of Medicinal Chemistry, Vol. 38, Issue 17 https://doi.org/10.1021/jm00017a015	journal	August 1995
Phosphinic Acid Analogs of GABA. 2. Selective, Orally Active GABAB Antagonists Froestl, Wolfgang; Mickel, Stuart J.; von Sprecher, Georg Journal of Medicinal Chemistry, Vol. 38, Issue 17 https://doi.org/10.1021/jm00017a016	journal	August 1995
A Mutual Prodrug Ester of GABA and Perphenazine Exhibits Antischizophrenic Efficacy with Diminished Extrapyramidal Effects Nudelman, Abraham; Gil-Ad, Irit; Shpaisman, Nava Journal of Medicinal Chemistry, Vol. 51, Issue 9 https://doi.org/10.1021/jm7012453	journal	March 2008
Discovery of a Negative Allosteric Modulator of GABA _B Receptors Chen, Lin-Hai; Sun, Bing; Zhang, Yang ACS Medicinal Chemistry Letters, Vol. 5, Issue 7 https://doi.org/10.1021/ml500162z	journal	May 2014
GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2 Jones, Kenneth A.; Borowsky, Beth; Tamm, Joe A. Nature, Vol. 396, Issue 6712 https://doi.org/10.1038/25348	journal	December 1998
Heterodimerization is required for the formation of a functional GABAB receptor White, Julia H.; Wise, Alan; Main, Martin J. Nature, Vol. 396, Issue 6712 https://doi.org/10.1038/25354	journal	December 1998
GABAB-receptor subtypes assemble into functional heteromeric complexes Kaupmann, Klemens; Malitschek, Barbara; Schuler, Valerie Nature, Vol. 396, Issue 6712 https://doi.org/10.1038/25360	journal	December 1998
(–)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor Bowery, N. G.; Hill, D. R.; Hudson, A. L. Nature, Vol. 283, Issue 5742 https://doi.org/10.1038/283092a0	journal	January 1980
3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain Hill, D. R.; Bowery, N. G. Nature, Vol. 290, Issue 5802 https://doi.org/10.1038/290149a0	journal	March 1981
A physiological role for GABAB receptors in the central nervous system Dutar, P.; Nicoll, R. A. Nature, Vol. 332, Issue 6160 https://doi.org/10.1038/332156a0	journal	March 1988
Structure and ligand recognition of class C GPCRs Chun, Lei; Zhang, Wen-hua; Liu, Jian-feng Acta Pharmacologica Sinica, Vol. 33, Issue 3 https://doi.org/10.1038/aps.2011.186	journal	January 2012
Characterization of ( R , S )-5,7-di- tert -butyl-3-hydroxy-3-trifluoromethyl-3 H -benzofuran-2-one as a positive allosteric modulator of GABA _B receptors: rac -BHFF: a positive modulator of GABA _B receptors Malherbe, P.; Masciadri, R.; Norcross, R. D. British Journal of Pharmacology, Vol. 154, Issue 4 https://doi.org/10.1038/bjp.2008.135	journal	June 2008
The oligomeric state sets GABA _B receptor signalling efficacy: Tetrameric GABA _B receptor signalling Comps-Agrar, Laëtitia; Kniazeff, Julie; Nørskov-Lauritsen, Lenea The EMBO Journal, Vol. 30, Issue 12 https://doi.org/10.1038/emboj.2011.143	journal	May 2011
Structural mechanism of ligand activation in human GABAB receptor Geng, Yong; Bush, Martin; Mosyak, Lidia Nature, Vol. 504, Issue 7479 https://doi.org/10.1038/nature12725	journal	December 2013
Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain Doré, Andrew S.; Okrasa, Krzysztof; Patel, Jayesh C. Nature, Vol. 511, Issue 7511 https://doi.org/10.1038/nature13396	journal	July 2014
Analysis of protein-coding genetic variation in 60,706 humans Lek, Monkol; Karczewski, Konrad J.; Minikel, Eric V. Nature, Vol. 536, Issue 7616 https://doi.org/10.1038/nature19057	journal	August 2016
Organization and functions of mGlu and GABAB receptor complexes Pin, Jean-Philippe; Bettler, Bernhard Nature, Vol. 540, Issue 7631 https://doi.org/10.1038/nature20566	journal	December 2016
A framework for the interpretation of de novo mutation in human disease Samocha, Kaitlin E.; Robinson, Elise B.; Sanders, Stephan J. Nature Genetics, Vol. 46, Issue 9 https://doi.org/10.1038/ng.3050	journal	August 2014
Structure and functional interaction of the extracellular domain of human GABAB receptor GBR2 Geng, Yong; Xiong, Dazhi; Mosyak, Lidia Nature Neuroscience, Vol. 15, Issue 7 https://doi.org/10.1038/nn.3133	journal	June 2012
Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics Schwenk, Jochen; Pérez-Garci, Enrique; Schneider, Andy Nature Neuroscience, Vol. 19, Issue 2 https://doi.org/10.1038/nn.4198	journal	December 2015
Regulation of neuronal GABAB receptor functions by subunit composition Gassmann, Martin; Bettler, Bernhard Nature Reviews Neuroscience, Vol. 13, Issue 6 https://doi.org/10.1038/nrn3249	journal	May 2012
Cryo-EM structures of inactive and active GABAB receptor Mao, Chunyou; Shen, Cangsong; Li, Chuntao Cell Research, Vol. 30, Issue 7 https://doi.org/10.1038/s41422-020-0350-5	journal	June 2020
Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing Dinamarca, Margarita C.; Raveh, Adi; Schneider, Andy Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-09164-3	journal	March 2019
Rearrangement of the transmembrane domain interfaces associated with the activation of a GPCR hetero-oligomer Xue, Li; Sun, Qian; Zhao, Han Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-10834-5	journal	June 2019
Structural basis for KCTD-mediated rapid desensitization of GABAB signalling Zheng, Sanduo; Abreu, Nohely; Levitz, Joshua Nature, Vol. 567, Issue 7746 https://doi.org/10.1038/s41586-019-0990-0	journal	February 2019
The mutational constraint spectrum quantified from variation in 141,456 humans Karczewski, Konrad J.; Francioli, Laurent C.; Tiao, Grace Nature, Vol. 581, Issue 7809 https://doi.org/10.1038/s41586-020-2308-7	journal	May 2020
Structural basis of the activation of a metabotropic GABA receptor Shaye, Hamidreza; Ishchenko, Andrii; Lam, Jordy Homing Nature, Vol. 584, Issue 7820 https://doi.org/10.1038/s41586-020-2408-4	journal	June 2020
Structure of human GABAB receptor in an inactive state Park, Jinseo; Fu, Ziao; Frangaj, Aurel Nature, Vol. 584, Issue 7820 https://doi.org/10.1038/s41586-020-2452-0	journal	June 2020
Structures of metabotropic GABAB receptor Papasergi-Scott, Makaía M.; Robertson, Michael J.; Seven, Alpay B. Nature, Vol. 584, Issue 7820 https://doi.org/10.1038/s41586-020-2469-4	journal	June 2020
Software tools for automated transmission electron microscopy Schorb, Martin; Haberbosch, Isabella; Hagen, Wim J. H. Nature Methods, Vol. 16, Issue 6 https://doi.org/10.1038/s41592-019-0396-9	journal	May 2019
Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction Punjani, Ali; Zhang, Haowei; Fleet, David J. Nature Methods, Vol. 17, Issue 12 https://doi.org/10.1038/s41592-020-00990-8	journal	November 2020
PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism Chang, Wenhan; Tu, Chia-Ling; Jean-Alphonse, Frederic G. Nature Metabolism, Vol. 2, Issue 3 https://doi.org/10.1038/s42255-020-0175-z	journal	March 2020
Subcellular distribution of GABAB receptor homo- and hetero-dimers Villemure, Josée-France; Adam, Lynda; Bevan, Nicola J. Biochemical Journal, Vol. 388, Issue 1 https://doi.org/10.1042/BJ20041435	journal	May 2005
Sushi domains confer distinct trafficking profiles on GABA _B receptors Hannan, Saad; Wilkins, Megan E.; Smart, Trevor G. Proceedings of the National Academy of Sciences, Vol. 109, Issue 30 https://doi.org/10.1073/pnas.1201660109	journal	July 2012
Heterodimeric coiled-coil interactions of human GABAB receptor Burmakina, S.; Geng, Y.; Chen, Y. Proceedings of the National Academy of Sciences, Vol. 111, Issue 19 https://doi.org/10.1073/pnas.1400081111	journal	April 2014
GABA _B(1) receptor subunit isoforms differentially regulate stress resilience O’Leary, Olivia F.; Felice, Daniela; Galimberti, Stefano Proceedings of the National Academy of Sciences, Vol. 111, Issue 42 https://doi.org/10.1073/pnas.1404090111	journal	October 2014
Stepwise activation of a class C GPCR begins with millisecond dimer rearrangement Grushevskyi, Eugene O.; Kukaj, Taulant; Schmauder, Ralf Proceedings of the National Academy of Sciences, Vol. 116, Issue 20 https://doi.org/10.1073/pnas.1900261116	journal	April 2019
Structural basis for auxiliary subunit KCTD16 regulation of the GABA _B receptor Zuo, Hao; Glaaser, Ian; Zhao, Yulin Proceedings of the National Academy of Sciences, Vol. 116, Issue 17 https://doi.org/10.1073/pnas.1903024116	journal	April 2019
Structural Analysis of the Complement Control Protein (CCP) Modules of GABAB Receptor 1a Blein, Stanislas; Ginham, Rachel; Uhrin, Dušan Journal of Biological Chemistry, Vol. 279, Issue 46 https://doi.org/10.1074/jbc.M406540200	journal	November 2004
Common Structural Requirements for Heptahelical Domain Function in Class A and Class C G Protein-coupled Receptors Binet, Virginie; Duthey, Béatrice; Lecaillon, Jennifer Journal of Biological Chemistry, Vol. 282, Issue 16 https://doi.org/10.1074/jbc.M611071200	journal	April 2007
Recent Advances in the Potential of Positive Allosteric Modulators of the GABAB Receptor to Treat Alcohol Use Disorder Augier, Eric Alcohol and Alcoholism, Vol. 56, Issue 2 https://doi.org/10.1093/alcalc/agab003	journal	February 2021
The ChEMBL bioactivity database: an update Bento, A. Patrícia; Gaulton, Anna; Hersey, Anne Nucleic Acids Research, Vol. 42, Issue D1 https://doi.org/10.1093/nar/gkt1031	journal	November 2013
PubChem 2019 update: improved access to chemical data Kim, Sunghwan; Chen, Jie; Cheng, Tiejun Nucleic Acids Research, Vol. 47, Issue D1 https://doi.org/10.1093/nar/gky1033	journal	October 2018
UniProt: a worldwide hub of protein knowledge Consortium, The UniProt Nucleic Acids Research https://doi.org/10.1093/nar/gky1049		November 2018
Heterochromatin protein 1α interacts with parallel RNA and DNA G-quadruplexes Roach, Ruby J.; Garavís, Miguel; González, Carlos Nucleic Acids Research, Vol. 48, Issue 2 https://doi.org/10.1093/nar/gkz1138	journal	December 2019
Evolutionary Relationships Among Proteins Encoded by the Regulator of Complement Activation Gene Cluster Krushkal, Julia; Bat, Olga; Gigli, Irma Molecular Biology and Evolution, Vol. 17, Issue 11 https://doi.org/10.1093/oxfordjournals.molbev.a026270	journal	November 2000
Cloning and functional characterization of a gamma‐hydroxybutyrate receptor identified in the human brain Andriamampandry, Christian; Taleb, Omar; Kemmel, Veronique The FASEB Journal, Vol. 21, Issue 3 https://doi.org/10.1096/fj.06-6509com	journal	December 2006
A Bayesian approach to beam-induced motion correction in cryo-EM single-particle analysis Zivanov, Jasenko; Nakane, Takanori; Scheres, Sjors H. W. IUCrJ, Vol. 6, Issue 1 https://doi.org/10.1107/S205225251801463X	journal	January 2019
Estimation of high-order aberrations and anisotropic magnification from cryo-EM data sets in RELION -3.1 Zivanov, Jasenko; Nakane, Takanori; Scheres, Sjors H. W. IUCrJ, Vol. 7, Issue 2 https://doi.org/10.1107/S2052252520000081	journal	February 2020
Isolation of Factor i Bazemore, A. W.; Elliott, K. A. C.; Florey, E. Journal of Neurochemistry, Vol. 1, Issue 4 https://doi.org/10.1111/j.1471-4159.1957.tb12090.x	journal	August 1957
Electrophysiological characterization of potent agonists and antagonists at pre- and postsynaptic GABAB receptors on neurones in rat brain slices Seabrook, G. R.; Howson, W.; Lacey, M. G. British Journal of Pharmacology, Vol. 101, Issue 4 https://doi.org/10.1111/j.1476-5381.1990.tb14186.x	journal	December 1990
The GABAB receptor as a target for antidepressant drug action: GABAB receptor expression and depression Ghose, Subroto; Winter, Michelle K.; McCarson, Kenneth E. British Journal of Pharmacology, Vol. 162, Issue 1 https://doi.org/10.1111/j.1476-5381.2010.01004.x	journal	December 2010
Biased signalling and allosteric machines: new vistas and challenges for drug discovery: 7TMRs as allosteric proteins Kenakin, Terry P. British Journal of Pharmacology, Vol. 165, Issue 6 https://doi.org/10.1111/j.1476-5381.2011.01749.x	journal	February 2012
Phenibut (β-Phenyl-GABA): A Tranquilizer and Nootropic Drug Lapin, Izyaslav CNS Drug Reviews, Vol. 7, Issue 4 https://doi.org/10.1111/j.1527-3458.2001.tb00211.x	journal	December 2001
Characterization of synaptically elicited GABAB responses using patch-clamp recordings in rat hippocampal slices. Otis, T. S.; De Koninck, Y.; Mody, I. The Journal of Physiology, Vol. 463, Issue 1 https://doi.org/10.1113/jphysiol.1993.sp019600	journal	April 1993
N , N ′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of γ-Aminobutyric Acid _B Receptor Function Urwyler, Stephan; Pozza, Mario F.; Lingenhoehl, Kurt Journal of Pharmacology and Experimental Therapeutics, Vol. 307, Issue 1 https://doi.org/10.1124/jpet.103.053074	journal	September 2003
Arbaclofen Placarbil, a Novel R -Baclofen Prodrug: Improved Absorption, Distribution, Metabolism, and Elimination Properties Compared with R -Baclofen Lal, Ritu; Sukbuntherng, Juthamas; Tai, Ezra H. L. Journal of Pharmacology and Experimental Therapeutics, Vol. 330, Issue 3 https://doi.org/10.1124/jpet.108.149773	journal	June 2009
Impact of the DRY Motif and the Missing “Ionic Lock” on Constitutive Activity and G-Protein Coupling of the Human Histamine H ₄ Receptor Schneider, Erich H.; Schnell, David; Strasser, Andrea Journal of Pharmacology and Experimental Therapeutics, Vol. 333, Issue 2 https://doi.org/10.1124/jpet.109.163220	journal	January 2010
Point Mutations in Either Subunit of the GABA _B Receptor Confer Constitutive Activity to the Heterodimer Mukherjee, Richa S.; McBride, Edward W.; Beinborn, Martin Molecular Pharmacology, Vol. 70, Issue 4 https://doi.org/10.1124/mol.106.024463	journal	July 2006
Ca ²⁺ Requirement for High-Affinity γ-Aminobutyric Acid (GABA) Binding at GABA _B Receptors: Involvement of Serine 269 of the GABA _B R1 Subunit Galvez, Thierry; Urwyler, Stephan; Prézeau, Laurent Molecular Pharmacology, Vol. 57, Issue 3 https://doi.org/10.1124/mol.57.3.419	journal	March 2000
Positive Allosteric Modulation of Native and Recombinant γ-Aminobutyric Acid _B Receptors by 2,6-Di- tert -butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its Aldehyde Analog CGP13501 Urwyler, Stephan; Mosbacher, Johannes; Lingenhoehl, Kurt Molecular Pharmacology, Vol. 60, Issue 5 https://doi.org/10.1124/mol.60.5.963	journal	November 2001
Harnessing Ion-Binding Sites for GPCR Pharmacology Zarzycka, Barbara; Zaidi, Saheem A.; Roth, Bryan L. Pharmacological Reviews, Vol. 71, Issue 4 https://doi.org/10.1124/pr.119.017863	journal	September 2019
International Union of Pharmacology. XXXIII. Mammalian gamma -Aminobutyric AcidB Receptors: Structure and Function Bowery, N. G. Pharmacological Reviews, Vol. 54, Issue 2 https://doi.org/10.1124/pr.54.2.247	journal	June 2002
Secreted amyloid-β precursor protein functions as a GABA _B R1a ligand to modulate synaptic transmission Rice, Heather C.; de Malmazet, Daniel; Schreurs, An Science, Vol. 363, Issue 6423 https://doi.org/10.1126/science.aao4827	journal	January 2019
Determination of the melanocortin-4 receptor structure identifies Ca ²⁺ as a cofactor for ligand binding Yu, Jing; Gimenez, Luis E.; Hernandez, Ciria C. Science, Vol. 368, Issue 6489 https://doi.org/10.1126/science.aaz8995	journal	April 2020
Serial Femtosecond Crystallography of G Protein–Coupled Receptors Stauch, Benjamin; Cherezov, Vadim Annual Review of Biophysics, Vol. 47, Issue 1 https://doi.org/10.1146/annurev-biophys-070317-033239	journal	May 2018
Molecular Mechanism of 7tm Receptor Activation—A Global Toggle Switch Model Schwartz, Thue W.; Frimurer, Thomas M.; Holst, Birgitte Annual Review of Pharmacology and Toxicology, Vol. 46, Issue 1 https://doi.org/10.1146/annurev.pharmtox.46.120604.141218	journal	February 2006
GHB for cataplexy: Possible mode of action Szabadi, Elemer Journal of Psychopharmacology, Vol. 29, Issue 6 https://doi.org/10.1177/0269881115573807	journal	March 2015
Evolution of the class C GPCR Venus flytrap modules involved positive selected functional divergence Cao, Jianhua; Huang, Siluo; Qian, Ji BMC Evolutionary Biology, Vol. 9, Issue 1 https://doi.org/10.1186/1471-2148-9-67	journal	January 2009
Evaluation of isonicotinoyl-.GAMMA.-aminobutyric acid (GABA) and nicotinoyl-GABA as pro-drugs of GABA. Matsuyama, Kenji; Yamashita, Chikamasa; Noda, Atsuko Chemical and Pharmaceutical Bulletin, Vol. 32, Issue 10 https://doi.org/10.1248/cpb.32.4089	journal	January 1984
GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities Enna, Sj Expert Opinion on Investigational Drugs, Vol. 6, Issue 10 https://doi.org/10.1517/13543784.6.10.1319	journal	October 1997
Patch-clamp recordings reveal powerful GABAergic inhibition in dentate hilar neurons Soltesz, I.; Mody, I. The Journal of Neuroscience, Vol. 14, Issue 4 https://doi.org/10.1523/JNEUROSCI.14-04-02365.1994	journal	April 1994
A Review of Spasticity Treatments: Pharmacological and Interventional Approaches Chang, Eric; Ghosh, Nilasha; Yanni, Daniel Critical Reviews in Physical and Rehabilitation Medicine, Vol. 25, Issue 1-2 https://doi.org/10.1615/CritRevPhysRehabilMed.2013007945	journal	January 2013
Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies Trzaskowski, B.; Latek, D.; Yuan, S. Current Medicinal Chemistry, Vol. 19, Issue 8 https://doi.org/10.2174/092986712799320556	journal	March 2012
GABA Receptors: Pharmacological Potential and Pitfalls Jembrek, Maja; Vlainic, Josipa Current Pharmaceutical Design, Vol. 21, Issue 34 https://doi.org/10.2174/1381612821666150914121624	journal	October 2015
Allosteric Modulators of GABAB Receptors: Mechanism of Action and Therapeutic Perspective Pin, Jean-Philippe; Prezeau, Laurent Current Neuropharmacology, Vol. 5, Issue 3 https://doi.org/10.2174/157015907781695919	journal	September 2007
Neurotransmitters as food supplements: the effects of GABA on brain and behavior Boonstra, Evert; de Kleijn, Roy; Colzato, Lorenza S. Frontiers in Psychology, Vol. 6 https://doi.org/10.3389/fpsyg.2015.01520	journal	October 2015
BL-1020, a New γ-Aminobutyric Acid–Enhanced Antipsychotic: Results of 6-Week, Randomized, Double-Blind, Controlled, Efficacy and Safety Study Geffen, Yona; Keefe, Richard; Rabinowitz, Jonathan The Journal of Clinical Psychiatry, Vol. 73, Issue 09 https://doi.org/10.4088/JCP.12m07642	journal	September 2012

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