Decarboxylation of Ang-(1–7) to Ala1-Ang-(1–7) leads to significant changes in pharmacodynamics

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dc.check.date2019-05-21
dc.check.infoAccess to this article is restricted until 12 months after publication by request of the publisher.en
dc.contributor.authorTetzner, Anja
dc.contributor.authorNaughton, Maura
dc.contributor.authorGebolys, Kinga
dc.contributor.authorEichhorst, Jenny
dc.contributor.authorSala, Esther
dc.contributor.authorVillacañas, Óscar
dc.contributor.authorWalther, Thomas
dc.contributor.funderDeutsche Forschungsgemeinschaften
dc.date.accessioned2018-06-05T09:30:25Z
dc.date.available2018-06-05T09:30:25Z
dc.date.issued2018-05-21
dc.date.updated2018-05-30T10:41:55Z
dc.description.abstractThe heptapeptide angiotensin (Ang)–(1–7) is part of the beneficial arm of the renin-angiotensin system. Ang-(1–7) has cardiovascular protective effects, stimulates regeneration, and opposes the often detrimental effects of Ang II. We recently identified the G protein-coupled receptors Mas and MrgD as receptors for the heptapeptide. Ala1-Ang-(1–7) (Alamandine), a decarboxylated form of Ang-(1–7), has similar vasorelaxant effects, but has been described to only stimulate MrgD. Therefore, this study aimed to characterise the consequences of the lack of the carboxyl group in amino acid 1 on intracellular signalling and to identify the receptor fingerprint for Ala1-Ang-(1–7). In primary endothelial and mesangial cells, Ala1-Ang-(1–7) elevated cAMP concentration. Dose response curves generated with Ang-(1–7) and Ala1-Ang-(1–7) significantly differed from each other, with a much lower EC50 and a bell-shape curve for Ala1-Ang-(1–7). We provided pharmacological proof that both, Mas and MrgD, are functional receptors for Ala1-Ang-(1–7). Consequently, in primary mesangial cells with genetic deficiency in both receptors the heptapeptide failed to increase cAMP concentration. As we previously described for Ang-(1–7), the Ala1-Ang-(1–7)-mediated cAMP increase in Mas/MrgD-transfected HEK293 cells and primary cells were blocked by the AT2 receptor blocker, PD123319. The very distinct dose-response curves for both heptapeptides could be explained by in silico modelling, electrostatic potential calculations, and an involvement of Galpha i for higher concentrations of Ala1-Ang-(1–7). Our results identify Ala1-Ang-(1–7) as a peptide with specific pharmacodynamic properties and build the basis for the design of more potent and efficient Ang-(1–7) analogues for therapeutic interventions in a rapidly growing number of diseases.en
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (WA1441/22-1; WA1441/22-2)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationTetzner, A., Naughton, M., Gebolys, K., Eichhorst, J., Sala, E., Villacañas, Ó and Walther, T. (2018) 'Decarboxylation of Ang-(1–7) to Ala1-Ang-(1–7) leads to significant changes in pharmacodynamics', European Journal of Pharmacology. doi:10.1016/j.ejphar.2018.05.031en
dc.identifier.doi10.1016/j.ejphar.2018.05.031
dc.identifier.issn0014-2999
dc.identifier.issn1879-0712
dc.identifier.journaltitleEuropean Journal of Pharmacologyen
dc.identifier.urihttps://hdl.handle.net/10468/6244
dc.language.isoenen
dc.publisherElsevier B.V.en
dc.rights© 2018, Elsevier B.V. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectDose-response curveen
dc.subjectG-proteinsen
dc.subjectMas receptoren
dc.subjectMrgD receptoren
dc.subjectRenin-angiotensin systemen
dc.subjectAla1-Angiotensin-(1–7)en
dc.titleDecarboxylation of Ang-(1–7) to Ala1-Ang-(1–7) leads to significant changes in pharmacodynamicsen
dc.typeArticle (peer-reviewed)en
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