|Nachman, Ronald - Ron|
Submitted to: Fly
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/18/2012
Publication Date: 12/15/2012
Citation: Chen, X., Peterson, J., Nachman, R.J., Ganetzky, B. 2012. Drosulfakinin activates CCKLR-17D1 and promotes larval locomotion and escape response in Drosophila. Fly. 6:290-297. Interpretive Summary: Insect pests have developed resistance to several conventional pesticides, and new approaches are needed for pest management. Although neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, the neuropeptides hold little promise as pest control agents because they can be degraded in the target pest. New, selective control agents may be developed by designing mimics of these neuropeptides that resist degradation and either inhibit or over-stimulate critical neuropeptide-regulated life functions. We need to investigate the complete spectrum of physiological/behavioral responses in insects regulated by specific classes of neuropeptides. We report on direct evidence that neuropeptides of the sulfakinin class engage an active site known as CCKLR-17D1. We further report the discovery that the sulfakinins and their active site (CCKLR-17D1) together promote larval body wall muscle contraction and are necessary for regulating the stress-induced escape response in the fruit fly, a model for important pest flies. Structural studies have identified factors important for the engagement of the sulfakinins with their active site. This discovery will aid in the design of neuropeptide-like compounds capable of disrupting both locomotion as well as behavioral responses that protect these and other flies from the adverse effects of environmental stress. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in the management of pest insects in an environmentally friendly fashion.
Technical Abstract: Neuropeptides are ubiquitous in both mammals and invertebrates and play essential roles in regulation and modulation of many developmental and physiological processes through activation of G-protein-coupled-receptors (GPCRs). However, the mechanisms by which many of the neuropeptides regulate specific neural function and behaviors remain undefined. Here we investigate the functions of Drosulfakinin (DSK), the Drosophila homolog of vertebrate neuropeptide cholecystokinin (CCK), which is the most abundant neuropeptide in the central nervous system. We provide direct evidence that sulfated DSK-1 and DSK-2 activate the CCKLR-17D1 receptor in a cell culture assay. We further examine the role of DSK and CCKLR-17D1 in the regulation of larval locomotion, both in a semi-intact larval preparation and in intact larvae under intense light exposure. Our results suggest that SDK/CCKLR-17D1 signaling promote larval body wall muscle contraction and is necessary for mediating locomotive behavior in stress-induced escape response.