Toxicology Letters 122 (2001) 215 – 222
GABA receptor subunit composition relative to insecticide
potency and selectivity
Gurpreet S. Ratra, John E. Casida *
Enironmental Chemistry and Toxicology Laboratory, Department of Enironmental Science, Policy and Management,
115 Wellman Hall, Uniersity of California, Berkeley, CA 94720 -3112, USA
Received 14 March 2001; received in revised form 20 April 2001; accepted 1 May 2001
Abstract
Three observations on the 4-[
3
H]propyl-4-ethynylbicycloorthobenzoate ([
3
H]EBOB) binding site in the -aminobu-
tyric acid (GABA) receptor indicate the specific target for insecticide action in human brain and a possible mechanism
for selectivity. First, from published data, -endosulfan, lindane and fipronil compete for the [
3
H]EBOB binding site
with affinities of 0.3 – 7 nM in both human recombinant homooligomeric 3 receptors and housefly head membranes.
Second, from structure-activity studies, including new data, GABAergic insecticide binding potency on the pentameric
receptor formed from the 3 subunit correlates well with that on the housefly receptor (r =0.88, n =20). This
conserved inhibitor specificity is consistent with known sequence homologies in the housefly GABA receptor and the
human GABA
A
receptor 3 subunit. Third, as mostly new findings, various combinations of 1, 6, and 2 subunits
coexpressed with a 1 or 3 subunit confer differential insecticide binding sensitivity, particularly to fipronil,
indicating that subunit composition is a major factor in insecticide selectivity. © 2001 Elsevier Science Ireland Ltd.
All rights reserved.
Keywords: -Aminobutryic acid; Binding site specificity; [
3
H]EBOB; -Endosulfan; Fipronil; GABA receptor; GABA receptor
subunits; Insecticide; Lindane; Subunit composition
www.elsevier.com/locate/toxlet
1. Introduction
Insecticides selectively toxic to insects compared
with humans play an essential role in crop protec-
tion and public health. One of their major targets
is the -aminobutyric acid (GABA)-gated chloride
channel. There are three major classes of
GABAergic insecticides exemplified by -endosul-
fan, lindane and fipronil (Fig. 1) (Casida, 1993;
Bloomquist, 2001). Selective toxicity is conferred
in part by target-site specificity between mammals
and insects (Cole and Casida, 1992; Hawkinson
and Casida, 1993; Casida and Pulman, 1994). The
mammalian GABA
A
pentameric receptor consists
primarily of heterooligomeric assemblies of
(1–6), (1–4), and (1 – 4) subunits. Recom-
binant subunits can be expressed individually or
in various combinations (some of which form
* Corresponding author. Tel.: +1-510-642-5424; fax: +1-
510-642-6497.
E-mail address: ectl@nature.berkeley.edu (J.E. Casida).
0378-4274/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII:S0378-4274(01)00366-6