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Title: Signalling properties and pharmacological analysis of two sulfakinin receptors from the red flour beetle, Tribolium castaneum

item ZELS, SVEN - Catholic University Of Leuven
item VERLINDEN, HELEEN - Catholic University Of Leuven
item DILLEN, SENNE - Catholic University Of Leuven
item VLEUGELS, RUT - Catholic University Of Leuven
item Nachman, Ronald
item VANDENBROECK, JOZEF - Catholic University Of Leuven

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/17/2014
Publication Date: 4/9/2014
Citation: Zels, S., Verlinden, H., Dillen, S., Vleugels, R., Nachman, R.J., Vandenbroeck, J. 2014. Signalling properties and pharmacological analysis of two sulfakinin receptors from the red flour beetle, Tribolium castaneum. PLoS One. 9(4):e9402.DOI:10.1371/journal.pone.0094502.

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. ‘Sulfakinin’ neuropeptides have been found to reduce food intake by up to 70% in the red flour beetle. In this study, two active sites for ‘sulfakinin’ neuropeptides were isolated and characterized from this pest of stored grain. The research also identified the location that the active sites occur in the central nervous system, molecular regions that operate as switches to turn them on or off, as well as the molecular pathways they follow once they are switched on by the sulfakinins. In addition, chemical characteristics required for successful interaction with the active site were delineated, along with novel mimics that are resistant to internal degradation within the pest. The discoveries revealed in this paper will aid in the design of neuropeptide-like compounds capable of disrupting both the feeding and digestive functions of pest insects.

Technical Abstract: Sulfakinin is an insect neuropeptide that constitutes an important component of the complex network of hormonal and neural factors that regulate feeding and digestion. The key modulating functions of sulfakinin are mediated by binding and signaling via G-protein coupled receptors. Although a substantial amount of functional data have already been reported on sulfakinins in different insect species, only little information is known regarding the properties of their respective receptors. In this study, we report on the molecular cloning, functional expression and characterization of two sulfakinin receptors in the red flour beetle, Tribolium castaneum. Both receptor open reading frames show extensive sequence similarity with annotated sulfakinin receptors from other insects. Comparison of the sulfakinin receptor sequences with homologous vertebrate cholecystokinin receptors reveals crucial conserved regions for ligand binding and receptor activation. Quantitative reverse transcriptase PCR shows that transcripts of both receptors are primarily expressed in the central nervous system of the beetle. Pharmacological characterization using 29 different peptide ligands clarified the essential requirements for efficient activation of these sulfakinin receptors. Analysis of the signaling pathway in multiple cell lines disclosed that the sulfakinin receptors of T. castaneum can stimulate both the Ca2+ and cyclic AMP second messenger pathways. This in depth characterization of two insect sulfakinin receptors may provide useful leads for the further development of receptor ligands with a potential applicability in pest control and crop protection.