MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries - Archive ouverte HAL
Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries

Abstract : All five muscarinic receptors have important physiological roles. The endothelial M2 and M3 subtypes regulate arterial tone through direct coupling to Gq or Gi/o proteins. Yet, we lack selective pharmacological drugs to assess the respective contribution of muscarinic receptors to a given function. We used mamba snake venoms to identify a selective M2R ligand to investigate its contribution to arterial contractions. Using a bio-guided screening binding assay, we isolated MT9 from the black mamba venom, a three-finger toxin active on the M2R subtype. After sequencing and chemical synthesis of MT9, we characterized its structure by X-ray diffraction and determined its pharmacological characteristics by binding assays, functional tests, and ex vivo experiments on rat and human arteries. Although MT9 belongs to the three-finger fold toxins family, it is phylogenetically apart from the previously discovered muscarinic toxins, suggesting that two groups of peptides evolved independently and in a convergent way to target muscarinic receptors. The affinity of MT9 for the M2R is 100 times stronger than that for the four other muscarinic receptors. It also antagonizes the M2R/G i pathways in cell-based assays. MT9 acts as a non-competitive antagonist against acetylcholine or arecaine, with low nM potency, for the activation of isolated rat mesenteric arteries. These results were confirmed on human internal mammary arteries. In conclusion, MT9 is the first fully characterized M2R-specific natural toxin. It should provide a tool for further understanding of the effect of M2R in various arteries and may position itself as a new drug candidate in cardiovascular diseases
Liste complète des métadonnées

https://hal.archives-ouvertes.fr/hal-03693311
Contributeur : Didier Boturyn Connectez-vous pour contacter le contributeur
Soumis le : vendredi 10 juin 2022 - 14:02:59
Dernière modification le : mardi 27 septembre 2022 - 04:22:28
Archivage à long terme le : : dimanche 11 septembre 2022 - 19:06:36

Fichier

Biomedicine & Pharmacotherapy ...
Publication financée par une institution

Identifiants

Citation

Justyna Ciolek, Claude Zoukimian, Justine Dhot, Mélanie Burban, Mathilde Triquigneaux, et al.. MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries. Biomedicine and Pharmacotherapy, Elsevier, 2022, 150, pp.113094. ⟨10.1016/j.biopha.2022.113094⟩. ⟨hal-03693311⟩

Partager

Métriques

Consultations de la notice

22

Téléchargements de fichiers

4