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.
???displayArticle.abstract???
Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(-)-4-amino-3-hydroxybutyric acid [R(-)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(-)- and S(+)-GABOB. The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes.
Accardi,
The Haemonchus contortus UNC-49B subunit possesses the residues required for GABA sensitivity in homomeric and heteromeric channels.
2011, Pubmed
Accardi,
The Haemonchus contortus UNC-49B subunit possesses the residues required for GABA sensitivity in homomeric and heteromeric channels.
2011,
Pubmed Accardi,
Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics.
2012,
Pubmed Alexander,
The Concise Guide to PHARMACOLOGY 2013/14: ligand-gated ion channels.
2013,
Pubmed Amin,
Homomeric rho 1 GABA channels: activation properties and domains.
1994,
Pubmed
,
Xenbase Amin,
GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital.
1993,
Pubmed
,
Xenbase Bamber,
Pharmacological characterization of the homomeric and heteromeric UNC-49 GABA receptors in C. elegans.
2003,
Pubmed
,
Xenbase Bamber,
The composition of the GABA receptor at the Caenorhabditis elegans neuromuscular junction.
2005,
Pubmed Bamber,
The Caenorhabditis elegans unc-49 locus encodes multiple subunits of a heteromultimeric GABA receptor.
1999,
Pubmed
,
Xenbase Beg,
EXP-1 is an excitatory GABA-gated cation channel.
2003,
Pubmed
,
Xenbase Brown,
Pharmacological characterization of the Haemonchus contortus GABA-gated chloride channel, Hco-UNC-49: modulation by macrocyclic lactone anthelmintics and a receptor for piperazine.
2012,
Pubmed
,
Xenbase Chebib,
Guanidino acids act as rho1 GABA(C) receptor antagonists.
2009,
Pubmed
,
Xenbase del Olmo,
Taurine activates GABA(A) but not GABA(B) receptors in rat hippocampal CA1 area.
2000,
Pubmed Dent,
avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans.
1997,
Pubmed Harrison,
Locating the carboxylate group of GABA in the homomeric rho GABA(A) receptor ligand-binding pocket.
2006,
Pubmed Hernando,
Caenorhabditis elegans neuromuscular junction: GABA receptors and ivermectin action.
2014,
Pubmed Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed Hinton,
Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABA(C) receptors.
2008,
Pubmed
,
Xenbase Holden-Dye,
ZAPA, (Z)-3-[(aminoiminomethyl)thio]-2-propenoic acid hydrochloride, a potent agonist at GABA-receptors on the Ascaris muscle cell.
1988,
Pubmed Holden-Dye,
GABA receptors on the somatic muscle cells of the parasitic nematode, Ascaris suum: stereoselectivity indicates similarity to a GABAA-type agonist recognition site.
1989,
Pubmed Hosie,
Agonist pharmacology of two Drosophila GABA receptor splice variants.
1996,
Pubmed
,
Xenbase Irwin,
ZINC: a free tool to discover chemistry for biology.
2012,
Pubmed Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed Kusama,
Pharmacology of GABA rho 1 and GABA alpha/beta receptors expressed in Xenopus oocytes and COS cells.
1993,
Pubmed
,
Xenbase Larkin,
Clustal W and Clustal X version 2.0.
2007,
Pubmed Martin,
Neuromuscular transmission in nematode parasites and antinematodal drug action.
1993,
Pubmed Martin,
Electrophysiological effects of piperazine and diethylcarbamazine on Ascaris suum somatic muscle.
1982,
Pubmed McGrath,
Guidelines for reporting experiments involving animals: the ARRIVE guidelines.
2010,
Pubmed McIntire,
Genes required for GABA function in Caenorhabditis elegans.
1993,
Pubmed Morris,
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.
2009,
Pubmed Neu,
Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism.
2002,
Pubmed
,
Xenbase Pawson,
The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands.
2014,
Pubmed Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed Pless,
A cation-π interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists.
2011,
Pubmed
,
Xenbase Richmond,
One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction.
1999,
Pubmed Roberts,
Different efficacies of d- and l-gamma-amino-beta-hydroxybutyric acids in GABA receptor and transport test systems.
1981,
Pubmed Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed Schuske,
The GABA nervous system in C. elegans.
2004,
Pubmed Siddiqui,
An UNC-49 GABA receptor subunit from the parasitic nematode Haemonchus contortus is associated with enhanced GABA sensitivity in nematode heteromeric channels.
2010,
Pubmed
,
Xenbase Thompson,
The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.
2012,
Pubmed
,
Xenbase Trott,
AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.
2010,
Pubmed Wagner,
An arginine involved in GABA binding and unbinding but not gating of the GABA(A) receptor.
2004,
Pubmed Wann,
The electrophysiology of the somatic muscle cells of Ascaris suum and Ascaridia galli.
1987,
Pubmed Woodward,
Characterization of bicuculline/baclofen-insensitive (rho-like) gamma-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of gamma-aminobutyric acidA and gamma-aminobutyric acidB receptor agonists and antagonists.
1993,
Pubmed
,
Xenbase Yamamoto,
Differentiating enantioselective actions of GABOB: a possible role for threonine 244 in the binding site of GABA(C) ρ(1) receptors.
2012,
Pubmed
,
Xenbase Yamamoto,
Structurally diverse GABA antagonists interact differently with open and closed conformational states of the ρ1 receptor.
2012,
Pubmed
,
Xenbase
