Variations in the Insect GABA Receptor, RDL, and Their Impact on Receptor Pharmacology

Abstract

The resistance to dieldrin (RDL) receptor is an insect γ-aminobutyric acid (GABA) receptor, characterized by the dieldrin resistance mutation that was pivotal to understanding target based insecticide resistance. RDL is the target for various non-competitive antagonists, including dieldrin and fipronil, as well as novel acting compounds such as the meta-diamides and isoxazolines. Therefore the RDL receptor has returned to center stage as a relevant and effective insecticide target. Our understanding of the function of RDL in vivo is still unfolding, with the discovery of species specific post-transcriptional modifications such as alternative splicing and RNA editing, modifications shown to influence the pharmacology of the receptor. Exposing these receptors to insecticides also evokes ever evolving mechanisms of mutagenesis, and a number of contributory mutations have been identified both in field and laboratory resistant insects, occurring in parallel to the dieldrin resistance mutation. We present an overview of these variations and discuss the impact on the pharmacology of GABA and various insecticides.

Spatiotemporally different expression of alternatively spliced GABA receptor subunit transcripts in the housefly Musca domestica

“…In contrast, invertebrate GABA receptors are composed of five subunits that are encoded by only a single gene, Rdl ( resistant to dieldrin ; ffrench‐Constant, Mortlock, Shaffer, MacIntyre, & Roush, ). However, they are diversified by gene duplication, alternative splicing, and RNA editing (Buckingham, Biggin, Sattelle, Brown, & Sattelle, ; Remnant et al, ; Taylor‐Wells & Jones, ; Yu, Cui, Lang, Zhang, & Zhang, ). For example, the Drosophila Rdl gene is alternatively spliced at exons 3 (a or b) and 6 (c or d) to yield four different transcripts with ac, ad, bc, and bd combinations (ffrench‐Constant & Rocheleau, ).…”

Genomics, cys-loop ligand-gated ion channels and new targets for the control of insect pests and vectors

“…Insect GABA receptors are the targets of several insecticide classes including cyclodienes, phenylpyrazoles and isoxazolines [24]. An alanine-to-serine mutation in the second transmembrane domain (A2'S) underlies resistance to cyclodienes, such as dieldrin [25][26][27]. A mutation at this site, either to serine or another residue such as glycine, has been commonly found in insecticide-resistant insects of diverse species.…”

“…A mutation at this site, either to serine or another residue such as glycine, has been commonly found in insecticide-resistant insects of diverse species. In some cases, mutations at other sites in RDL have been identified although always together with the TM2 mutation [26][27][28]. The mutation at the A2 site, therefore, is commonly used as a diagnostic marker for resistance.…”

“…Xenopus laevis oocytes giving the impression that it is a relatively simple receptor. This impression, however, is likely to be false as alternative splicing and RNA A-to-I editing of Rdl transcripts can considerably increase receptor diversity [27]. Recently, it has been shown that RNA A-to-I editing, which can alter up to six amino acid residues in An.…”

How Complex Can Resistance to Dieldrin, the Insect γ-Aminobutyric Acid Receptor, Get?

“…4 In addition to this, differential use of splice acceptor sites generates RDL variants with differing lengths of an intracellular domain. 5,6 Furthermore, in some species, RDL diversity is expanded through A-to-I editing. 7,8 Here, certain adenosine residues in pre-mRNA are changed to inosine by adenosine deaminases that remove an amine group.…”