Functional Characterisation of insect nicotinic Acetylcholine Receptors

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By 2050 it is estimated that the global population will have increased by a third. The calorific requirements to sustain this population will need to increase by 50% and, with a growing preference for meat consumption, additional provision of feedstocks will also be needed. It has been estimated that this will require a 70% increase in crop yields by 2050. Thus increasing demands will be placed on available agricultural land to deliver efficient, reliable and sustainable food production. Insecticides are important tools for ensuring efficient crop yields. New insecticides need to be created on a regular basis to overcome resistance in pest populations as well as providing more benign environmental impacts and human safety profiles. In particular, new insecticides need to exhibit low toxicity to non-target species, particularly the major pollinators such as bees, while retaining efficacy against both the 'chewing' and 'sucking' pests that can devastate many major crops. The target of the most commercially important insecticides is the neuronal acetylcholine signalling pathway and of this class of insecticides, the safest and most effective are molecules (neonicotinoids and spinosyns) that act at the nicotinic acetylcholine receptor (nAChR). The nAChR is in fact composed of five protein subunits that form a complex. In the well established model insect, the fruit fly Drosophila melanogaster, there are ten different genes encoding nAChR subunit proteins, and these can combine to form many different classes of nAChRs, each with the potential to interact differently with insecticidal compounds. To date, very little is known about how these subunits combine, what other proteins act as accessory molecules interacting with receptor subunits, or what impact the 'parts list' of each complex has on its pharmacological properties. The aim of this project is to characterise functionally distinct classes of nAChRs in Drosophila melanogaster, a genetically and biochemically tractable insect model system that will generate insights broadly applicable to other insect species. Knowledge of the functional classes of nAChRs in Drosophila will pave the way for more targeted future research in the pest insects that cause havoc to major crops and for which there are currently very few genetics tools. In this application we will apply cutting edge spatial proteomics methods created by Kathryn Lilley with insect gene editing and advanced genetics techniques available from Steve Russell to advance the insect receptor biochemical and pharmacological approaches established at Syngenta, one of the world's leading agrochemical companies. Together, the proposed research programme will lead to a thorough characterisation of different native nAChR classes and substantially advance our understanding of a class of insecticide targets that are crucial for protecting global agriculture. The ability to design effective new insecticides that are safe and have low environmental impact will be essential to the continuing drive to increase agricultural yields and better feed the growing global population.