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Title: SUBSTITUTION OF CONSERVED GLYCINE RESIDUE BY ALANINE IN NATURAL AND SYNTHETIC NEUROPEPTIDE LIGANDS CAUSES PARTIAL AGONISM AT THE STOMOXYTACHYKININ RECEPTOR

Author
item POELS, JEROEN - CATHOLIC UNIV, BELGIUM
item VAN LOY, TOM - CATHOLIC UNIV, BELGIUM
item FRANSSENS, VANESSA - CATHOLIC UNIV, BELGIUM
item DETHEUX, MICHEL - CATHOLIC UNIV, BELGIUM
item Nachman, Ronald
item OONK, HENDRICA - CATHOLIC UNIV, BELGIUM
item AKERMAN, KARL - UPPSALA UNIV, SWEDEN
item VASSART, GILBERT - CATHOLIC UNIV, BELGIUM
item PARMENTIER, MARC - CATHOLIC UNIV, BELGIUM
item DE LOOF, ARNOLD - CATHOLIC UNIV, BELGIUM
item TORFS, HERBERT - CATHOLIC UNIV, BELGIUM
item VANDEN BROECK, JOZEF - CATHOLIC UNIV, BELGIUM

Submitted to: Journal of Neurochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/15/2004
Publication Date: 6/14/2004
Citation: Poels, J., Van Loy, T., Franssens, V., Detheux, M., Nachman, R.J., Oonk, H.B., Akerman, K.E., Vassart, G., Parmentier, M., De Loof, A., Torfs, H., Vanden Broeck, J. 2004. Substitution of conserved glycine residue by alanine in natural and synthetic neuropeptide ligands causes partial agonism at the stomoxytachykinin receptor. Journal of Neurochemistry. 90:472-478.

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 insect pests. The basic premise of this research is that neuropeptides (short chains of amino acids) serve as potent internal messengers in insects to regulate vital functions such as water balance and digestion in flies. New, selective control measures may be developed by designing metabolically stable mimics of these neuropeptides that actively inhibit or over-stimulate functions regulated by them, resulting in disruption of the internal environment of the insect. We report on an evaluation of the effects of a rare, naturally-occurring structural variant within the core region of the 'insectatachykinins,' neuropeptides that regulate aspects of water balance and digestion, on the ability to 'turn on' the active site in livestock pest, the stable fly. The results indicate that two different, but equally viable, pathways exist to 'turn on' the active site, leading to different outcomes in the regulation of life functions critical to insect survival. A deeper understanding of structural requirements for neuropeptide action in insects will aid in the design of neuropeptide mimics capable of interfering with critical life functions in pest flies. The work brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling pest insects in an environmentally friendly fashion.

Technical Abstract: A few naturally occurring insect tachykinin-related peptides, such as stomoxytachykinin (Stc-TK), contain an Ala-residue instead of the highly conserved Gly-residue that is present in most other members of this peptide family. Stc-TK is a potent, partial antagonist of the stable fly (Stomoxys calcitrans) tachykinin receptor, STKR. By means of synthetic analogues, the Gly/Ala exchange, representing the addition of a single methyl group in the active core region of these peptides, was shown to be fully responsible for the generation of this partial agonism., which was also accompanied by an increase in agonistic potency. Surprisingly, this Ala-dependent reduction in maximal response levels was only observed for the agonist-induced cellular calcium rise. Stomoxytachykinin, Stc-TK, did not display partial agonism for the STKR-dedicated cyclic AMP response. A possible explanation for this differential partial agonism is that the Gly-containing and Ala-replaced peptides recognize and stabilize action receptor conformations that differ in their functional coupling efficacies towards these response pathways. Drosotachykinins, Drm-TK, tachykinin-like peptides encoded in the fruit fly genome, were shown to be STKR-agonists. Interestingly, one of these peptides, which contains an Ala-residue instead of the conserved Gly-residue, also proved to be a potent, partial agonist for STKR.