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.

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

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 Allosteric Modulation of Ligand Gated Ion Channels by Ivermectin

2014 ◽  
pp. S215-S224 ◽  
Author(s):  
H. ZEMKOVA ◽  
V. TVRDONOVA ◽  
A. BHATTACHARYA ◽  
M. JINDRICHOVA
Keyword(s):  
Ion Channels ◽  
Binding Site ◽  
Glycine Receptor ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Structural Determinants ◽  
P2x4 Receptor ◽  
Electrophysiological Recordings ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

Ivermectin acts as a positive allosteric regulator of several ligand-gated channels including the glutamate-gated chloride channel (GluCl),  aminobutyric acid type-A receptor, glycine receptor, neuronal α7-nicotinic receptor and purinergic P2X4 receptor. In most of the ivermectin-sensitive channels, the effects of ivermectin include the potentiation of agonist-induced currents at low concentrations and channel opening at higher concentrations. Based on mutagenesis, electrophysiological recordings and functional analysis of chimeras between ivermectin-sensitive and ivermectin-insensitive receptors, it has been concluded that ivermectin acts by insertion between transmembrane helices. The three-dimensional structure of C. elegans GluCl complexed with ivermectin has revealed the details of the ivermectin-binding site, however, no generic motif of amino acids could accurately predict ivermectin binding site for other ligand gated channels. Here, we will review what is currently known about ivermectin binding and modulation of Cys-loop receptor family of ligand-gated ion channels and what are the critical structural determinants underlying potentiation of the P2X4 receptor channel.

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 γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs

2016 ◽  
Vol 124 (3) ◽  
pp. 651-663 ◽  
Author(s):  
Ervin Pejo ◽  
Peter Santer ◽  
Lei Wang ◽  
Philip Dershwitz ◽  
S. Shaukat Husain ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Response Curve ◽  
Type A ◽  
Field Analysis ◽  
Aminobutyric Acid ◽  
Molecular Field ◽  
Comparative Molecular Field Analysis ◽  
Structural Elements ◽  
Receptor Modulation ◽  
Acid Type

Abstract Background Etomidate is a highly potent anesthetic agent that is believed to produce hypnosis by enhancing γ-aminobutyric acid type A (GABAA) receptor function. The authors characterized the GABAA receptor and hypnotic potencies of etomidate analogs. The authors then used computational techniques to build statistical and graphical models that relate the potencies of these etomidate analogs to their structures to identify the specific molecular determinants of potency. Methods GABAA receptor potencies were defined with voltage clamp electrophysiology using α1β3γ2 receptors harboring a channel mutation (α1[L264T]) that enhances anesthetic sensitivity (n = 36 to 60 measurements per concentration–response curve). The hypnotic potencies of etomidate analogs were defined using a loss of righting reflexes assay in Sprague Dawley rats (n = 9 to 21 measurements per dose–response curve). Three-dimensional quantitative structure–activity relationships were determined in silico using comparative molecular field analysis. Results The GABAA receptor and hypnotic potencies of etomidate and the etomidate analogs ranged by 91- and 53-fold, respectively. These potency measurements were significantly correlated (r2 = 0.72), but neither measurement correlated with drug hydrophobicity (r2 = 0.019 and 0.005, respectively). Statistically significant and predictive comparative molecular field analysis models were generated, and a pharmacophore model was built that revealed both the structural elements in etomidate analogs associated with high potency and the interactions that these elements make with the etomidate-binding site. Conclusions There are multiple specific structural elements in etomidate and etomidate analogs that mediate GABAA receptor modulation. Modifying any one element can alter receptor potency by an order of magnitude or more.

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
Sign in / Sign up

Export Citation Format

Share Document