The Brugia malayi neuropeptide receptor-4 is activated by FMRFamide-like peptides and signals via Gαi

• We have cloned a neuropeptide G protein-coupled receptor (GPCR) from Brugia malayi.
• The GPCR displays homology with C. elegans NPR-4.
• B. malayi NPR-4 is activated by FMRFamide-like peptide-18 (FLP-18) ligands.
• NPR-4 signals via a pertussis toxin-sensitive Gαi mediated pathway.
• Helminth GPCR signalling is a valid target for therapeutic intervention.

Genetic studies undertaken in the model organism Caenorhabditis elegans have demonstrated the importance of neuropeptidergic signalling in nematode physiology. Disruption of this signalling may have deleterious phenotypic consequences, including altered locomotion, feeding behaviour, and reproduction. Neuropeptide G protein-coupled receptors (GPCRs) that transduce many of these signals therefore represent cogent drug targets. Recently published genomic sequencing data for a number of parasitic helminths of medical and veterinary importance has revealed the apparent conservation of a number of neuropeptides, and neuropeptide receptors between parasitic and free-living species, raising the intriguing possibility of developing broad-spectrum anthelmintic therapeutics. Here, we identify and clone a neuropeptide receptor, NPR-4, from the human filarial nematode Brugia malayi and demonstrate its activation in vitro, by FMRFamide-like peptides of the FLP-18 family, and intracellular signalling via Gαi mediated pathways. These data represent the first example of deorphanisation of a neuropeptide GPCR in any parasitic helminth species.

Figure optionsDownload high-quality image (171 K)Download as PowerPoint slide