IMR Press / FBL / Volume 27 / Issue 5 / DOI: 10.31083/j.fbl2705150
Open Access Original Research
Structure-Activity Relationship Data and Ligand-Receptor Interactions Identify Novel Agonists Consistent with Sulfakinin Tissue-Specific Signaling in Drosophila Melanogaster Heart
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1 Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0660, USA
*Correspondence: (Ruthann Nichols)
These authors contributed equally.
Academic Editor: Graham Pawelec
Front. Biosci. (Landmark Ed) 2022, 27(5), 150;
Submitted: 3 January 2022 | Revised: 27 January 2022 | Accepted: 9 February 2022 | Published: 10 May 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: The structures and activities of invertebrate sulfakinins that influence gut motility and heart rate are like the vertebrate cholecystokinin (CCK) peptides. Typical of sulfakinin precursors Drosophila melanogaster encodes non-sulfated drosulfakinin I (nsDSK I; FDDYGHMRF-NH2) and nsDSK II (GGDDQFDDYGHMRF-NH2) that bind DSK-R1 and DSK-R2. To explore the role of the nsDSK II N-terminal extension (GGDDQ) in gut we delineated its structure-activity relationship (SAR) and identified novel agonists. We then predicted the nsDSK II extension SAR is tissue specific consistent with cardiac CCK structure activity and signaling being different from gut. Methods: To evaluate our hypothesis, we tested single-substituted alanine and asparagine analogs in heart. Results: We found alanyl-substituted analogs were less active in heart than nsDSK II; in gut they include a super agonist and a protean agonist. Additionally, we discovered ns[N4]DSK II was more active than nsDSK II in pupal heart, while ns[N3]DSK II was inactive. In contrast, ns[N3]DSK II and ns[N4]DSK II were super agonists in adult heart, yet inactive in larva. Although we reported nsDSK II acts through DSK-R2 in gut, its identity in heart was unknown. Conclusions: Here we reviewed ligand-receptor interactions in conjunction with SAR data to suggest nsDSK II acts through DSK-R1 in heart consistent with sulfakinin tissue-specific signaling.

FMRFamide-related peptide
Fig. 1.
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