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Article Dans Une Revue International Journal of Molecular Sciences Année : 2023

Characterization of the First Animal Toxin Acting as an Antagonist on AT1 Receptor

Anne-Cécile van Baelen
  • Fonction : Auteur
Xavier Iturrioz
Marion Chaigneau
  • Fonction : Auteur
Pascal Kessler
  • Fonction : Auteur
Catherine Llorens-Cortes
  • Fonction : Auteur
Nicolas Gilles
Philippe Robin
  • Fonction : Auteur

Résumé

The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and β-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, β-arrestin 2 pathways and ERK1/2 activation. These results describe the first animal toxin active on angiotensin II receptors.

Dates et versions

hal-04456586 , version 1 (14-02-2024)

Identifiants

Citer

Anne-Cécile van Baelen, Xavier Iturrioz, Marion Chaigneau, Pascal Kessler, Catherine Llorens-Cortes, et al.. Characterization of the First Animal Toxin Acting as an Antagonist on AT1 Receptor. International Journal of Molecular Sciences, 2023, 24 (3), pp.2330. ⟨10.3390/ijms24032330⟩. ⟨hal-04456586⟩
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