Horoszok L et al. (2001), GLC-3: a novel fipronil and BIDN-sensitive, but...

XB-ART-9393

Br J Pharmacol 2001 Mar 01;1326:1247-54. doi: 10.1038/sj.bjp.0703937.

Show Gene links Show Anatomy links

GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from Caenorhabditis elegans.

Horoszok L , Raymond V , Sattelle DB , Wolstenholme AJ .

???displayArticle.abstract???
1. We report the cloning and expression of a novel Caenorhabditis elegans polypeptide, GLC-3, with high sequence identity to previously cloned L-glutamate-gated chloride channel subunits from nematodes and insects. 2. Expression of glc-3 cRNA in XENOPUS oocytes resulted in the formation of homo-oligomeric L-glutamate-gated chloride channels with robust and rapidly desensitizing currents, an EC(50) of 1.9+/-0.03 mM and a Hill coefficient of 1.5+/-0.1. GABA, glycine, histamine and NMDA all failed to activate the GLC-3 homo-oligomer at concentrations of 1 mM. The anthelminthic, ivermectin, directly and irreversibly activated the L-glutamate-gated channel with an EC(50) of 0.4+/-0.02 microM. 3. The GLC-3 channels were selective for chloride ions, as shown by the shift in the reversal potential for L-glutamate-gated currents after the reduction of external Cl(-) from 107.6 to 62.5 mM. 4. Picrotoxinin failed to inhibit L-glutamate agonist responses at concentrations up to 1 mM. The polycyclic dinitrile, 3,3-bis-trifluoromethyl-bicyclo[2,2,1]heptane-2,2-dicarbonitrile (BIDN), completely blocked L-glutamate-induced chloride currents recorded from oocytes expressing GLC-3 with an IC(50) of 0.2+/-0.07 microM. The phenylpyrazole insecticide, fipronil, reversibly inhibited L-glutamate-gated currents recorded from the GLC-3 receptor with an IC(50) of 11.5+/-0.11 microM. 5. In this study, we detail the unusual antagonist pharmacology of a new GluCl subunit from C. elegans. Unlike all other native and recombinant nematode GluCl reported to date, the GLC-3 receptor is insensitive to picrotoxinin, but is sensitive to two other channel blockers, BIDN and fipronil. Further study of this receptor may provide insights into the molecular basis of non-competitive antagonism by these compounds.

???displayArticle.pubmedLink??? 11250875
???displayArticle.pmcLink??? PMC1572670
???displayArticle.link??? Br J Pharmacol

Species referenced: Xenopus laevis
Genes referenced: bag3

References [+] :

Arena, The mechanism of action of avermectins in Caenorhabditis elegans: correlation between activation of glutamate-sensitive chloride current, membrane binding, and biological activity. 1995, Pubmed , Xenbase
Arena, Expression of a glutamate-activated chloride current in Xenopus oocytes injected with Caenorhabditis elegans RNA: evidence for modulation by avermectin. 1992, Pubmed , Xenbase
Bargmann, Neurobiology of the Caenorhabditis elegans genome. 1998, Pubmed
Bloomquist, Toxicology, mode of action and target site-mediated resistance to insecticides acting on chloride channels. 1993, Pubmed
Casida, Insecticide action at the GABA-gated chloride channel: recognition, progress, and prospects. 1993, Pubmed
C. elegans Sequencing Consortium, Genome sequence of the nematode C. elegans: a platform for investigating biology. 1998, Pubmed
Cleland, Inhibitory glutamate receptor channels. 1996, Pubmed
Cull-Candy, Two types of extrajunctional L-glutamate receptors in locust muscle fibres. 1976, Pubmed
Cully, Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. 1994, Pubmed , Xenbase
Cully, Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin. 1996, Pubmed , Xenbase
Dent, The genetics of ivermectin resistance in Caenorhabditis elegans. 2000, Pubmed
Dent, avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans. 1997, Pubmed
Etter, Picrotoxin blockade of invertebrate glutamate-gated chloride channels: subunit dependence and evidence for binding within the pore. 1999, Pubmed , Xenbase
Ffrench-Constant, A point mutation in a Drosophila GABA receptor confers insecticide resistance. 1993, Pubmed , Xenbase
Gurley, Point mutations in the M2 region of the alpha, beta, or gamma subunit of the GABAA channel that abolish block by picrotoxin. 1995, Pubmed , Xenbase
Hamon, BIDN, a bicyclic dinitrile convulsant, selectively blocks GABA-gated Cl- channels. 1998, Pubmed , Xenbase
Hosie, Actions of the insecticide fipronil, on dieldrin-sensitive and- resistant GABA receptors of Drosophila melanogaster. 1995, Pubmed , Xenbase
Hosie, Actions of picrodendrin antagonists on dieldrin-sensitive and -resistant Drosophila GABA receptors. 1996, Pubmed , Xenbase
Hosie, Blocking actions of BIDN, a bicyclic dinitrile convulsant compound, on wild-type and dieldrin-resistant GABA receptor homo-oligomers of Drosophila melanogaster expressed in Xenopus oocytes. 1995, Pubmed , Xenbase
Hosie, Molecular biology of insect neuronal GABA receptors. 1997, Pubmed
Laughton, Alternative splicing of a Caenorhabditis elegans gene produces two novel inhibitory amino acid receptor subunits with identical ligand binding domains but different ion channels. 1997, Pubmed
Lynch, Mutations affecting the glycine receptor agonist transduction mechanism convert the competitive antagonist, picrotoxin, into an allosteric potentiator. 1995, Pubmed
Olsen, Molecular biology of GABAA receptors. 1990, Pubmed
Pribilla, The atypical M2 segment of the beta subunit confers picrotoxinin resistance to inhibitory glycine receptor channels. 1992, Pubmed
Ranganathan, MOD-1 is a serotonin-gated chloride channel that modulates locomotory behaviour in C. elegans. 2000, Pubmed , Xenbase
Rauh, Effects of [3H]-BIDN, a novel bicyclic dinitrile radioligand for GABA-gated chloride channels of insects and vertebrates. 1997, Pubmed , Xenbase
Smith, Functional domains of GABAA receptors. 1995, Pubmed
Vassilatis, Genetic and biochemical evidence for a novel avermectin-sensitive chloride channel in Caenorhabditis elegans. Isolation and characterization. 1997, Pubmed , Xenbase
Wang, A single amino acid in gamma-aminobutyric acid rho 1 receptors affects competitive and noncompetitive components of picrotoxin inhibition. 1995, Pubmed , Xenbase
Xu, Interaction of picrotoxin with GABAA receptor channel-lining residues probed in cysteine mutants. 1995, Pubmed , Xenbase
Zhang, Subunit composition determines picrotoxin and bicuculline sensitivity of Drosophila gamma-aminobutyric acid receptors. 1995, Pubmed , Xenbase
Zhang, A unique amino acid of the Drosophila GABA receptor with influence on drug sensitivity by two mechanisms. 1994, Pubmed