|Nachman, Ronald - Ron|
Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/3/2008
Publication Date: 6/14/2008
Citation: Janssen, T., Meelkop, E., Lindemans, M., Verstraelen, K., Husson, S.J., Temmerman, L., Nachman, R.J., Schoofs, L. 2008. Discovery of a cholecystokinin-gastrin like signaling system in nematodes. Endocrinology. 144:2826-2839. 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. The basic premise of this research is that ‘sulfakinin’ neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate satiety and other vital functions. Nevertheless, these neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest, and inability 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 in such a way as 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 labeled ‘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, including nematode worms and insects, 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. Despite many efforts following the discovery of CCK/gastrin immunoreactivity in nematodes 23 years ago, the identity of these nematode CCK/gastrin related peptides has remained a mystery ever since. The C. elegans genome contains two genes with high identity to the mammalian CCK receptors and their invertebrate counterparts, the sulfakinin receptors. By using the potential C. elegans CCK receptors as a fishing hook, we have isolated and identified two CCK-like neuropeptides encoded by NLP-12 as the endogenous ligands of these receptors. The NLP-12 peptides have a very limited neuronal expression pattern, seem to occur in vivo in the unsulfated form, and react specifically with a human CCK-8 antibody. Both receptors and ligands share a high degree of structural 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 gastrin-CCK signaling system was already well established prior to the divergence of Protostomes and Deuterostomes.