Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2012 Feb 24;2879:6714-24. doi: 10.1074/jbc.M111.316836.
Show Gene links
Show Anatomy links
Structural link between γ-aminobutyric acid type A (GABAA) receptor agonist binding site and inner β-sheet governs channel activation and allosteric drug modulation.
Venkatachalan SP
,
Czajkowski C
.
???displayArticle.abstract???
Rapid opening and closing of pentameric ligand-gated ion channels (pLGICs) regulate information flow throughout the brain. For pLGICs, it is postulated that neurotransmitter-induced movements in the extracellular inner β-sheet trigger channel activation. Homology modeling reveals that the β4-β5 linker physically connects the neurotransmitter binding site to the inner β-sheet. Inserting 1, 2, 4, and 8 glycines in this region of the GABA(A) receptor β-subunit progressively decreases GABA activation and converts the competitive antagonist SR-95531 into a partial agonist, demonstrating that this linker is a key element whose length and flexibility are optimized for efficient signal propagation. Insertions in the α- and γ-subunits have little effect on GABA or SR-95531 actions, suggesting that asymmetric motions in the extracellular domain power pLGIC gating. The effects of insertions on allosteric modulator actions, pentobarbital, and benzodiazepines, have different subunit dependences, indicating that modulator-induced signaling is distinct from agonist gating.
Akabas,
GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures.
2004, Pubmed
Akabas,
GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures.
2004,
Pubmed
Akk,
Activation and block of recombinant GABA(A) receptors by pentobarbitone: a single-channel study.
2000,
Pubmed
Amin,
A single hydrophobic residue confers barbiturate sensitivity to gamma-aminobutyric acid type C receptor.
1999,
Pubmed
Amin,
GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital.
1993,
Pubmed
,
Xenbase
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Bocquet,
A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family.
2007,
Pubmed
,
Xenbase
Boileau,
Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric gamma-aminobutyric acidA receptor subunits.
1998,
Pubmed
,
Xenbase
Boileau,
GABA(A) receptor beta 2 Tyr97 and Leu99 line the GABA-binding site. Insights into mechanisms of agonist and antagonist actions.
2002,
Pubmed
,
Xenbase
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Buhr,
A point mutation in the gamma2 subunit of gamma-aminobutyric acid type A receptors results in altered benzodiazepine binding site specificity.
1997,
Pubmed
,
Xenbase
Cadugan,
Linking the acetylcholine receptor-channel agonist-binding sites with the gate.
2010,
Pubmed
Campo-Soria,
Mechanism of action of benzodiazepines on GABAA receptors.
2006,
Pubmed
,
Xenbase
Chakrapani,
The role of loop 5 in acetylcholine receptor channel gating.
2003,
Pubmed
Cheng,
Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.
1973,
Pubmed
Chou,
Relationships between inhibition constants and fractional inhibition in enzyme-catalyzed reactions with different numbers of reactants, different reaction mechanisms, and different types and mechanisms of inhibition.
1974,
Pubmed
Dellisanti,
Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution.
2007,
Pubmed
Downing,
Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABA(A) receptors supports an allosteric model of modulation.
2005,
Pubmed
Duncalfe,
The major site of photoaffinity labeling of the gamma-aminobutyric acid type A receptor by [3H]flunitrazepam is histidine 102 of the alpha subunit.
1996,
Pubmed
Gao,
Agonist-mediated conformational changes in acetylcholine-binding protein revealed by simulation and intrinsic tryptophan fluorescence.
2005,
Pubmed
Goldschen-Ohm,
An epilepsy-related region in the GABA(A) receptor mediates long-distance effects on GABA and benzodiazepine binding sites.
2010,
Pubmed
Hanek,
Photochemical proteolysis of an unstructured linker of the GABAAR extracellular domain prevents GABA but not pentobarbital activation.
2010,
Pubmed
Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed
Henchman,
Ligand-induced conformational change in the alpha7 nicotinic receptor ligand binding domain.
2005,
Pubmed
Henchman,
Asymmetric structural motions of the homomeric alpha7 nicotinic receptor ligand binding domain revealed by molecular dynamics simulation.
2003,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed
Hilf,
X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
2008,
Pubmed
Holden,
Different residues in the GABA(A) receptor alpha 1T60-alpha 1K70 region mediate GABA and SR-95531 actions.
2002,
Pubmed
,
Xenbase
Jackson,
Single channel currents activated by gamma-aminobutyric acid, muscimol, and (-)-pentobarbital in cultured mouse spinal neurons.
1982,
Pubmed
Jones,
Defining affinity with the GABAA receptor.
1998,
Pubmed
Kloda,
Agonist-, antagonist-, and benzodiazepine-induced structural changes in the alpha1 Met113-Leu132 region of the GABAA receptor.
2007,
Pubmed
,
Xenbase
Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase
Mercado,
Gamma-aminobutyric acid (GABA) and pentobarbital induce different conformational rearrangements in the GABA A receptor alpha1 and beta2 pre-M1 regions.
2008,
Pubmed
,
Xenbase
Mercado,
Charged residues in the alpha1 and beta2 pre-M1 regions involved in GABAA receptor activation.
2006,
Pubmed
,
Xenbase
Mihic,
A single amino acid of the human gamma-aminobutyric acid type A receptor gamma 2 subunit determines benzodiazepine efficacy.
1994,
Pubmed
,
Xenbase
Miller,
Mapping a molecular link between allosteric inhibition and activation of the glycine receptor.
2008,
Pubmed
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Mourot,
Agonist- and competitive antagonist-induced movement of loop 5 on the alpha subunit of the neuronal alpha4beta4 nicotinic acetylcholine receptor.
2008,
Pubmed
,
Xenbase
Newell,
The GABAA receptor alpha 1 subunit Pro174-Asp191 segment is involved in GABA binding and channel gating.
2003,
Pubmed
,
Xenbase
Pistis,
Complementary regulation of anaesthetic activation of human (alpha6beta3gamma2L) and Drosophila (RDL) GABA receptors by a single amino acid residue.
1999,
Pubmed
,
Xenbase
Price,
A hydrogen bond in loop A is critical for the binding and function of the 5-HT3 receptor.
2008,
Pubmed
Purohit,
A stepwise mechanism for acetylcholine receptor channel gating.
2007,
Pubmed
Robinson,
Optimizing the stability of single-chain proteins by linker length and composition mutagenesis.
1998,
Pubmed
Rosen,
Channel opening by anesthetics and GABA induces similar changes in the GABAA receptor M2 segment.
2007,
Pubmed
Rüsch,
Classic benzodiazepines modulate the open-close equilibrium in alpha1beta2gamma2L gamma-aminobutyric acid type A receptors.
2005,
Pubmed
,
Xenbase
Sancar,
Allosteric modulators induce distinct movements at the GABA-binding site interface of the GABA-A receptor.
2011,
Pubmed
,
Xenbase
Serafini,
Structural domains of the human GABAA receptor 3 subunit involved in the actions of pentobarbital.
2000,
Pubmed
Sharkey,
Individually monitoring ligand-induced changes in the structure of the GABAA receptor at benzodiazepine binding site and non-binding-site interfaces.
2008,
Pubmed
,
Xenbase
Szarecka,
Dynamics of heteropentameric nicotinic acetylcholine receptor: implications of the gating mechanism.
2007,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Walters,
Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms.
2000,
Pubmed
,
Xenbase
