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Title: FUNCTIONAL ANALYSIS OF SYNTHETIC INSECTATACHYKININ ANALOGS OF RECOMBINANT NEUROKININ RECEPTOR EXPRESSING CELLS

Author
item TORFS, HERBERT - CATHOLIC UNIV, BELGIUM
item AKERMAN, KARL - CATHOLIC UNIV, BELGIUM
item Nachman, Ronald
item OONK, HENDRIKA - CATHOLIC UNIV, BELGIUM
item DETHEUX, MICHEL - CATHOLIC UNIV, BELGIUM
item POELS, JEROEN - CATHOLIC UNIV, BELGIUM
item VAN LOY, TOM - CATHOLIC UNIV, BELGIUM
item DELOOF, ARNOLD - CATHOLIC UNIV, BELGIUM
item MELEON, ROB - CATHOLIC UNIV, BELGIUM
item VASSART, GILBERT - CATHOLIC UNIV, BELGIUM

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/6/2002
Publication Date: 10/1/2002
Citation: Torfs, H., Akerman, K.E., Nachman, R.J., Oonk, H.B., Detheux, M., Poels, J., Van Loy, T., Deloof, A., Meleon, R.H., Vassart, G. 2002. Functional analysis of synthetic insectatachykinin analogs of recombinant neurokinin receptor expressing cells. Peptides. 23(11):1999-2005.

Interpretive Summary: Neuropeptides are short chains of amino acids (the building blocks of proteins) that regulate aspects of reproduction, development and digestion that are critical for insect survival. Nevertheless, these insect peptides in and of themselves hold little promise as insect control agents because of susceptibility to being degraded in the target insect, and inability to pass through the outside skin (cuticle) and/or digestive tract of the insect. We must design neuropeptide mimics that resist degradation by enzymes in the digestive tract and blood of pest insects and enter efficiently via a topical or oral route. We report on the identification of portions of the peptide that are critical for activation of the active site within the insect, and those portions which can discriminate between active sites in insects versus mammals. This information will aid in the development of enzyme-resistant mimics capable of disrupting neuropeptide-regulated processes in insects. 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: The activity of a series of synthetic tachykinin-like peptide analogs was studied by means of microscopic calcium imaging on recombinant neurokinin receptor expressing cell lines. A C-terminal pentapeptide (FTGMRa) is sufficient for activation of the stomoxytachykinin receptor (STKR) expressed in Schneider 2 cells. Replacement of amino acid residues at the position of the conserved phenylalanine (F) or arginine (R) residues by alanine (A) results in inactive peptides (when tested at 1 uM), whereas A-replacements of other positions do not abolish the biological activity of the resulting insectatachykinin-like analogs. Calcium imaging was also employed to compare the activity of C-terminally substituted tachykinin analogs on three different neurokinin receptors. The results indicate that the major pharmacological and evolutionary difference between tachykinin-related agonists for insect (STKR) and human (NK1 and NK2) receptors resides in the C-terminal amino acid residues (R versus M). A single C-terminal amino acid change can turn an STKR-agonist into an NK agonist and vice versa.