scholarly journals Proximity-accelerated Chemical Coupling Reaction in the Benzodiazepine-binding Site of γ-Aminobutyric Acid Type A Receptors

2007 ◽  
Vol 282 (36) ◽  
pp. 26316-26325 ◽  
Author(s):  
Kelly R. Tan ◽  
Anne Gonthier ◽  
Roland Baur ◽  
Margot Ernst ◽  
Maurice Goeldner ◽  
...  
Keyword(s):  
Binding Site ◽  
Coupling Reaction ◽  
Type A ◽  
Aminobutyric Acid ◽  
Acid Type ◽  
Benzodiazepine Binding ◽  
Chemical Coupling

scholarly journals Identification of the Bovine γ-Aminobutyric Acid Type A Receptor α Subunit Residues Photolabeled by the Imidazobenzodiazepine [3H]Ro15-4513

2002 ◽  
Vol 277 (51) ◽  
pp. 50036-50045 ◽  
Author(s):  
Gregory W. Sawyer ◽  
David C. Chiara ◽  
Richard W. Olsen ◽  
Jonathan B. Cohen
Keyword(s):  
Amino Acids ◽  
Sequence Analysis ◽  
Binding Site ◽  
Type A ◽  
Homology Model ◽  
Aminobutyric Acid ◽  
Modulate Function ◽  
Α Subunit ◽  
Acid Type ◽  
Benzodiazepine Binding

Ligands binding to the benzodiazepine-binding site in γ-aminobutyric acid type A (GABAA) receptors may allosterically modulate function. Depending upon the ligand, the coupling can either be positive (flunitrazepam), negative (Ro15-4513), or neutral (flumazenil). Specific amino acid determinants of benzodiazepine binding affinity and/or allosteric coupling have been identified within GABAAreceptor α and γ subunits that localize the binding site at the subunit interface. Previous photolabeling studies with [3H]flunitrazepam identified a primary site of incorporation at α1His-102, whereas studies with [3H]Ro15-4513 suggested incorporation into the α1subunit at unidentified amino acids C-terminal to α1His-102. To determine the site(s) of photoincorporation by Ro15-4513, we affinity-purified (∼200-fold) GABAAreceptor from detergent extracts of bovine cortex, photolabeled it with [3H]Ro15-4513, and identified3H-labeled amino acids by N-terminal sequence analysis of subunit fragments generated by sequential digestions with a panel of proteases. The patterns of3H release seen after each digestion of the labeled fragments determined the number of amino acids between the cleavage site and labeled residue, and the use of sequential proteolytic fragmentation identified patterns of cleavage sites unique to the different α subunits. Based upon this radiochemical sequence analysis, [3H]Ro15-4513 was found to selectively label the homologous tyrosines α1Tyr-210, α2Tyr-209, and α3Tyr-234, in GABAAreceptors containing those subunits. These results are discussed in terms of a homology model of the benzodiazepine-binding site based on the molluscan acetylcholine-binding protein structure.

Structural elements involved in activation of the γ-aminobutyric acid type A (GABAA) receptor

2004 ◽  
Vol 32 (3) ◽  
pp. 540-546 ◽  
Author(s):  
T.L. Kash ◽  
J.R. Trudell ◽  
N.L. Harrison
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Binding Site ◽  
Type A ◽  
Aminobutyric Acid ◽  
Structural Elements ◽  
Agonist Binding ◽  
Acid Type ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Ligand-gated ion channels function as rapid signal transducers, converting chemical signals (in the form of neurotransmitters) into electrical signals in the postsynaptic neuron. This is achieved by the recognition of neurotransmitter at its specific-binding sites, which then triggers the opening of an ion channel (‘gating’). For this to occur rapidly (<1 ms), there must be an efficient coupling between the agonist-binding site and the gate, located more than 30 Å (1 Å=0.1 nm) away. Whereas a great deal of progress has been made in elucidating the structure and function of both the agonist-binding site and the ion permeation pathway in ligand-gated ion channels, our knowledge of the coupling mechanism between these domains has been limited. In this review, we summarize recent studies of the agonist-binding site and the ion channel in the γ-aminobutyric acid type A receptor, and discuss those structural elements that may mediate coupling between them. We will also consider some possible molecular mechanisms of receptor activation.

5-(Piperidin-4-yl)-3-Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ-Aminobutyric Acid Type A Receptor Binding Site

ChemMedChem ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. 2475-2485 ◽  
Author(s):  
Jacob Krall ◽  
Kenneth T. Kongstad ◽  
Birgitte Nielsen ◽  
Troels E. Sørensen ◽  
Thomas Balle ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Binding Site ◽  
Acid Type ◽  
Novel Scaffold

scholarly journals A Conserved Tyrosine in the β2Subunit M4 Segment Is a Determinant of γ-Aminobutyric Acid Type A Receptor Sensitivity to Propofol

2007 ◽  
Vol 107 (3) ◽  
pp. 412-418 ◽  
Author(s):  
James E. Richardson ◽  
Paul S. Garcia ◽  
Kate K. O'Toole ◽  
Jason M. C. Derry ◽  
Shannon V. Bell ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
General Anesthetics ◽  
Receptor Function ◽  
293 Cells ◽  
Acid Type ◽  
Normal Sensitivity

Background The gamma-aminobutyric acid type A receptor (GABAA-R) beta subunits are critical targets for the actions for several intravenous general anesthetics, but the precise nature of the anesthetic binding sites are unknown. In addition, little is known about the role the fourth transmembrane (M4) segment of the receptor plays in receptor function. The aim of this study was to better define the propofol binding site on the GABAA-R by conducting a tryptophan scan in the M4 segment of the beta2 subunit. Methods Seven tryptophan mutations were introduced into the C-terminal end of the M4 segment of the GABAA-R beta2 subunit. GABAA-R subunit complementary DNAs were transfected into human embryonic kidney 293 cells grown on glass coverslips. After transfection (36-72 h), coverslips were transferred to a perfusion chamber to assay receptor function. Cells were whole cell patch clamped and exposed to GABA, propofol, etomidate, and pregnenolone. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger. Results All tryptophan mutations were well tolerated, and with one exception, all resulted in minimal changes in receptor activation by GABA. One mutation, beta2(Y444W), selectively suppressed the ability of propofol to enhance receptor function while retaining normal sensitivity to etomidate and pregnenolone. Conclusions This is the first report of a mutation that selectively reduces propofol sensitivity without altering the action of etomidate. The reduction in propofol sensitivity is consistent with the loss of a hydrogen bond within the propofol binding site. These results also suggest a possible orientation of the propofol molecule within its binding site.

scholarly journals Gephyrin-mediated γ-Aminobutyric Acid Type A and Glycine Receptor Clustering Relies on a Common Binding Site

2011 ◽  
Vol 286 (49) ◽  
pp. 42105-42114 ◽  
Author(s):  
Hans-Michael Maric ◽  
Jayanta Mukherjee ◽  
Verena Tretter ◽  
Stephen J. Moss ◽  
Hermann Schindelin
Keyword(s):  
Binding Site ◽  
Glycine Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Clustering ◽  
Acid Type

scholarly journals Mapping General Anesthetic Binding Site(s) in Human α1β3 γ-Aminobutyric Acid Type A Receptors with [3H]TDBzl-Etomidate, a Photoreactive Etomidate Analogue

Biochemistry ◽  
2012 ◽  
Vol 51 (4) ◽  
pp. 836-847 ◽  
Author(s):  
David C. Chiara ◽  
Zuzana Dostalova ◽  
Selwyn S. Jayakar ◽  
Xiaojuan Zhou ◽  
Keith W. Miller ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Aminobutyric Acid ◽  
General Anesthetic ◽  
Acid Type
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