GPCR day, Solvay Pharmaceuticals location:Weesp, The Netherlands date:12 December 2008
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 (~satiety) 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 bait, we have isolated and identified two CCK-like neuropeptides encoded by a peptideprecursor protein called 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. The elucidation of the receptor expression pattern is underway. 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. Many research centers including major pharmaceutical companies like GlaxoSmithKline, AstraZenica and Sanofi-Aventis have initiated programs with the aim to identify “small molecules” with selective CCK1R agonist activity as potential anti-obesity drugs. However, despite many efforts, it has been shown that CCK1R monotherapy is ineffective against obesity. The exact reason for this remains unclear, but a possible explanation poses that compensatory mechanisms come into play in long-term studies that are not seen in short-term experiments. To solve this, a better understanding of the mechanisms by which cholecystokinin regulates orexigenic pathways in the body is essential. C. elegans has great potential as a model to uncover the processes that govern metabolic physiology and allows high-throughput screening in a physiological context, which can bridge the gap between traditional in vitro and preclinical animal assays.