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Titolo:
Role of human GABA(A) receptor beta 3 subunit in insecticide toxicity
Autore:
Ratra, GS; Kamita, SG; Casida, JE;
Indirizzi:
Univ Calif Berkeley, Dept Environm Sci Policy & Management, Environm Chem & Toxicol Lab, Berkeley, CA 94720 USA Univ Calif Berkeley Berkeley CA USA 94720 col Lab, Berkeley, CA 94720 USA Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA Univ Calif Davis Davis CA USA 95616 is, Dept Entomol, Davis, CA 95616 USA
Titolo Testata:
TOXICOLOGY AND APPLIED PHARMACOLOGY
fascicolo: 3, volume: 172, anno: 2001,
pagine: 233 - 240
SICI:
0041-008X(20010501)172:3<233:ROHGRB>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMINOBUTYRIC ACID(A) RECEPTORS; GATED CHLORIDE CHANNEL; TERT-BUTYLBICYCLOPHOSPHOROTHIONATE RECEPTOR; ALLOSTERIC LIGANDS; BINDING-SITES; A RECEPTORS; BICYCLOPHOSPHORUS ESTERS; PYRETHROID INSECTICIDES; FUNCTIONAL EXPRESSION; ALPHA-SUBUNIT;
Keywords:
beta 3 homooligomer; alpha-endosulfan insecticide; fipronil insecticide; GABA-stimulated chloride uptake; GABA(A) receptor; insecticide toxicity; lindane insecticide; subunit composition;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Casida, JE Univ Calif Berkeley, Dept Environm Sci Policy & Management, Environm Chem & Toxicol Lab, Berkeley, CA 94720 USA Univ Calif Berkeley Berkeley CA USA 94720 rkeley, CA 94720 USA
Citazione:
G.S. Ratra et al., "Role of human GABA(A) receptor beta 3 subunit in insecticide toxicity", TOX APPL PH, 172(3), 2001, pp. 233-240

Abstract

The gamma -aminobutyric acid type A (GABA(A)) receptor is the target for the major insecticides alpha -endosulfan, lindane, and fipronil and for manyanalogs. Their action as chloride channel blockers is directly measured bybinding studies with [H-3]ethynylbicycloorthobenzoate ([H-3]EBOB). This study tests the hypothesis that GABA(A) receptor subunit composition determines the sensitivity and selectivity of insecticide toxicity. Human receptor subtypes were expressed individually (alpha1, alpha6, beta1, beta3, and gamma2) and in combination in insect Sf9 cells. Binding parameters were similar for [H-3]EBOB in the beta3 homooligomer, alpha1 beta3 gamma2 heterooligomer, and native brain membranes, but toxicological profiles were very different. Surprisingly, alpha -endosulfan, lindane, and fipronil were all remarkably potent on the recombinant beta3 homooligomeric receptor (IC50 values of 0.5-2.4 nM), whereas they were similar in potency on the alpha1 beta3 gamma2 subtype (IC50 values of 16-33 nM) and highly selective on the native receptor (IC50 values of 7.3, 306, and 2470 nM, respectively). The selectivity order for 29 insecticides and convulsants as IC50 ratios for native/beta3or alpha1 beta3 gamma2/beta3 was as follows: fipronil > lindane > 19 otherinsecticides including alpha -endosulfan and picrotoxinin > 4 trioxabicyclooctanes and dithianes (almost nonselective) > tetramethylenedisulfotetramine, 4-chlorophenylsilatrane, or alpha -thujone, Specificity between mammalsand insects at the target site (fipronil > lindane > alpha -endosulfan) paralleled that for toxicity. Potency at the native receptor is more predictive for inhibition of GABA-stimulated chloride uptake than that at the beta3or alpha1 beta3 gamma2 receptors, Therefore, the beta3 subunit contains the insecticide target and other subunits differentially modulate the bindingto confer compound-dependent specificity and selective toxicity. (C) 2001 Academic Press.

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Documento generato il 20/09/20 alle ore 09:41:51