Development of a human vasopressin V1a-receptor antagonist from an evolutionary-related insect neuropeptide

Di Giglio, Maria G and Muttenthaler, Markus and Harpsøe, Kasper and Liutkeviciute, Zita and Keov, Peter and Eder, Thomas and Rattei, Thomas and Arrowsmith, Sarah and Wray, Susan and Marek, Ales and Elbert, Tomas and Alewood, Paul F and Gloriam, David E and Gruber, Christian W (2017) Development of a human vasopressin V1a-receptor antagonist from an evolutionary-related insect neuropeptide. Scientific Reports, 7. Article number: 41002 . ISSN 20452322

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Abstract

Characterisation of G protein-coupled receptors (GPCR) relies on the availability of a toolbox of ligands that selectively modulate different functional states of the receptors. To uncover such molecules, we explored a unique strategy for ligand discovery that takes advantage of the evolutionary conservation of the 600-million-year-old oxytocin/vasopressin signalling system. We isolated the insect oxytocin/vasopressin orthologue inotocin from the black garden ant (Lasius niger), identified and cloned its cognate receptor and determined its pharmacological properties on the insect and human oxytocin/vasopressin receptors. Subsequently, we identified a functional dichotomy: inotocin activated the insect inotocin and the human vasopressin V1b receptors, but inhibited the human V1aR. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V1aR-antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V1aR over the other three subtypes, OTR, V1bR and V2R. The Arg8/D-Arg8 ligand-pair was further investigated to gain novel insights into the oxytocin/vasopressin peptide-receptor interaction, which led to the identification of key residues of the receptors that are important for ligand functionality and selectivity. These observations could play an important role for development of oxytocin/vasopressin receptor modulators that would enable clear distinction of the physiological and pathological responses of the individual receptor subtypes.

Item Type: Article
DOI: 10.1038/srep41002
Uncontrolled Keywords: Pharmacology; entomology; peptides receptor
Subjects: 500 Science > 570 Life sciences; biology > 576 Genetics and evolution
500 Science > 590 Animals (zoology) > 592 Invertebrates
Research Group: Cremer Group
SWORD Depositor: Sword Import User
Depositing User: Sword Import User
Date Deposited: 10 Mar 2017 07:36
Last Modified: 30 Aug 2017 09:42
URI: https://repository.ist.ac.at/id/eprint/790

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