Development of a human vasopressin V 1a -receptor antagonist from an evolutionary-related insect neuropeptide

Maria Giulia Di Giglio, Markus Muttenthaler, Kasper Harpsøe, Zita Liutkeviciute, Peter Keov, Thomas Eder, Thomas Rattei, Sarah Arrowsmith, Susan Wray, Ales Marek, Tomas Elbert, Paul F. Alewood, David E. Gloriam, Christian W. Gruber

Research output: Contribution to journalArticleResearchpeer-review

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 V 1b receptors, but inhibited the human V 1a R. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V 1a R-Antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V 1a R over the other three subtypes, OTR, V 1b R and V 2 R. 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.

Original languageEnglish
Article number41002
Number of pages15
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 1 Feb 2017
Externally publishedYes

Cite this

Di Giglio, M. G., Muttenthaler, M., Harpsøe, K., Liutkeviciute, Z., Keov, P., Eder, T., ... Gruber, C. W. (2017). Development of a human vasopressin V 1a -receptor antagonist from an evolutionary-related insect neuropeptide. Scientific Reports, 7, [41002]. https://doi.org/10.1038/srep41002
Di Giglio, Maria Giulia ; Muttenthaler, Markus ; Harpsøe, Kasper ; Liutkeviciute, Zita ; Keov, Peter ; Eder, Thomas ; Rattei, Thomas ; Arrowsmith, Sarah ; Wray, Susan ; Marek, Ales ; Elbert, Tomas ; Alewood, Paul F. ; Gloriam, David E. ; Gruber, Christian W. / Development of a human vasopressin V 1a -receptor antagonist from an evolutionary-related insect neuropeptide. In: Scientific Reports. 2017 ; Vol. 7.
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Di Giglio, MG, Muttenthaler, M, Harpsøe, K, Liutkeviciute, Z, Keov, P, Eder, T, Rattei, T, Arrowsmith, S, Wray, S, Marek, A, Elbert, T, Alewood, PF, Gloriam, DE & Gruber, CW 2017, 'Development of a human vasopressin V 1a -receptor antagonist from an evolutionary-related insect neuropeptide' Scientific Reports, vol. 7, 41002. https://doi.org/10.1038/srep41002

Development of a human vasopressin V 1a -receptor antagonist from an evolutionary-related insect neuropeptide. / Di Giglio, Maria Giulia; Muttenthaler, Markus; Harpsøe, Kasper; Liutkeviciute, Zita; Keov, Peter; Eder, Thomas; Rattei, Thomas; Arrowsmith, Sarah; Wray, Susan; Marek, Ales; Elbert, Tomas; Alewood, Paul F.; Gloriam, David E.; Gruber, Christian W.

In: Scientific Reports, Vol. 7, 41002, 01.02.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Liutkeviciute, Zita

AU - Keov, Peter

AU - Eder, Thomas

AU - Rattei, Thomas

AU - Arrowsmith, Sarah

AU - Wray, Susan

AU - Marek, Ales

AU - Elbert, Tomas

AU - Alewood, Paul F.

AU - Gloriam, David E.

AU - Gruber, Christian W.

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