Functional analysis of insect neuropeptide G protein-coupled receptors.

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To stay alive, organisms must continuously tune their various functions according to their internal and external environment. In multicellular organisms, the complex task of regulating the different tissues (lung, heart, liver, etc) is handled by chemical messengers (acetylcholine, insulin, etc) that bind to particular receptor proteins on, or in, the appropriate targets cells for such messages. In humans, the design of drugs that affect these receptors (GPCRs) - and thus alter the tuning of our bodies - is a huge area for the pharmaceutical industry, and major research programmes have given us some of the world's most widely used drugs for a range of disease (like high blood pressure or depression). Such GPCRs are no less important in insects, and as many of the world's most dangerous diseases (like malaria, dengue and Zika) are vectored by insects. With as many species as all other forms of life combined, it is inevitable that arthropods - and particularly insects - impinge on our lives in both positive and negative ways. They impact food security, both as pollinators and as destroyers of the world's crops; and also animal health, as vectors of animal and human disease. Climate change moves these threats ever closer to the UK, as evidenced by recent UK cases of blue tongue virus and the presence of alien insect crop pest species. Although there is a remarkable range of pesticides in use today to control insect pests, significantly, resistance to all classes of pesticides by insects is a serious problem, and few new insecticides have been brought to market in recent years. Furthermore, ever tighter regulatory controls require removal of useful compounds from our insect control repertoire. There is thus a need for a better understanding of insect physiology and environmental stress tolerance, so that we can identify new, more selective (and thus 'greener') ways of controlling them. As such, drugs impacting insect GPCRs have the potential to be new, more selective insect control agents. Here, we bring together a range of world-leading expertise and emerging technologies in this cross-disciplinary project between Life Sciences and Chemistry to address this issue. We will provide a deeper underdertanding of how these GPCRs signal in insects and also how they enable insects to withstand environmental stress for survival by developing new tools for use in an organismal context, based on the fruit fly, Drosophila melanogaster. We will also develop new small protein 'mimetics' which act on GPCRs (similar in function to the endogenous small proteins which activate GPCRs) that may be developed towards a new class of insect control agents which do not engender insect resistance, and which do not threaten the environment.