G protein coupled receptors as targets for next generation pesticides.

There is an on-going need for the discovery and development of new pesticides due to the loss of existing products through the continuing development of resistance, the desire for products with more favourable environmental and toxicological profiles and the need to implement the principles of integrated pest management. Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behaviour, including reproduction, osmoregulation, growth and development. Modifying normal receptor function by blocking or over stimulating its actions may either result in the death of a pest or disrupt its normal fitness or reproductive capacity to reduce pest populations. Hence GPCRs offer potential targets for the development of next generation pesticides providing opportunities to discover new chemistries for invertebrate pest control. Such receptors are important targets for pharmaceutical drugs, but are under-exploited by the agro-chemical industry. The octopamine receptor agonists are the only pesticides with a recognized mode of action, as described in the classification scheme developed by the Insecticide Resistance Action Committee, that act via a GPCR. The availability of sequenced insect genomes has facilitated the characterization of insect GPCRs, but the development and utilization of screening assays to identify lead compounds has been slow. Various studies using knock-down technologies or applying the native ligands and/or neuropeptide analogues to pest insects in vivo, have however demonstrated that modifying normal receptor function can have an insecticidal effect. This review presents examples of potential insect neuropeptide receptors that are potential targets for lead compound development, using case studies from three representative pest species, Tribolium castaneum, Acyrthosiphon pisum, and Drosophila suzukii. Functional analysis studies on T. castaneum suggest that GPCRs involved in growth and development (eclosion hormone, ecdysis triggering hormone and crustacean cardioacceleratory peptide receptors) as well as the dopamine-2 like, latrophilin-like, starry night, frizzled-like, methuselah-like and the smoothened receptors may be suitable pesticide targets. From in vivo studies using native ligands and peptide analogues, receptors which appear to have a role in the regulation of feeding in the pea aphid, such as the PISCF-allatostatin and the various "kinin" receptors, are also potential targets. In Drosophila melanogaster various neuropeptides and their signalling pathways have been studied extensively. This may provide insights into potential pesticide targets that could be exploited in D. suzukii. Examples include the sex peptide receptor, which is involved in reproduction and host seeking behaviours, and those responsible for osmoregulation such as the diuretic hormone receptors. However the neuropeptides and their receptors in insects are often poorly characterized, especially in pest species. Although data from closely related species may be transferable (e.g. D. melanogaster to D. suzukii), peptides and receptors may have different roles in different insects, and hence a target in one insect may not be appropriate in another. Hence fundamental knowledge of the roles and functions of receptors is vital for development to proceed.