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Title: Evolutionary conservation of the cholecystokinin/gastrin signaling system in nematodes

item Nachman, Ronald

Submitted to: Annals of the New York Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/14/2008
Publication Date: 4/28/2009
Citation: Janssen, T., Meelkop, E., Nachman, R.J., Schoofs, L. 2009. Evolutionary conservation of the cholecystokinin/gastrin signaling system in nematodes. Annals of the New York Academy of Sciences. 1163:428-432.

Interpretive Summary: Because of problems with the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling invertebrate pests such as insects and nematode worms. Although “sulfakinin” neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, these natural neuropeptides hold little promise as pest control agents because they are susceptible to degradation in the target pest, and are unable to pass through the outside skin and/or digestive tract. We must design neuropeptide mimics that resist degradation by enzymes in the digestive tract and blood of pest invertebrates and interact with the active site within an agricultural or medical pest to either over-activate or block critical, neuropeptide-regulated life functions. We report on the isolation, identification, and characterization of “sulfakinin” invertebrate neuropeptides from the nematode, C. elegans, a prime model for parasitic nematode worms that plague man, livestock, and crops. The structures of these neuropeptides and their active sites suggest that the sulfakinin regulatory system is a very ancient one, predating the split between vertebrates and invertebrates. The discovery of the specific nematode “sulfakinin” structure will aid in the design of neuropeptide-like compounds capable of disrupting critical life functions in nematode worms. This work represents a spin-off of our primary focus on insect pests and brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling invertebrate pests in an environmentally friendly fashion.

Technical Abstract: Members of the cholecystokinin/gastrin family of peptides, including the arthropod sulfakinins, and their cognate receptors, play an important role in the regulation of feeding behavior and energy homeostasis. By using the potential C. elegans CCK receptors as bait, we have isolated and identified two CCK-like neuropeptides as the endogenous ligands of these nematode receptors. Both receptors and ligands share a high degree of sequence similarity with their vertebrate and arthropod counterparts and also display similar biological activities with respect to digestive enzyme secretion and fat storage. Our data indicate that the CCK/gastrin signaling system was already well established prior to the divergence of protostomes and deuterostomes.