The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release.

Autor: Neasta J; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Valmalle C; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Coyne AC; INSERM UMR 952, Physiopathologie des Maladies du Système Nerveux Central, Paris, France., Carnazzi E; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Subra G; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Galleyrand JC; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Gagne D; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., M'Kadmi C; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Bernad N; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Bergé G; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Cantel S; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Marin P; Institut de Génomique Fonctionnelle, UMR5203, INSERM U661, Rue de la Cardonille, Université de Montpellier, Montpellier, France., Marie J; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Banères JL; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Kemel ML; CIRB, Collège de France, 11, Place Marcelin Berthelot, Paris, France., Daugé V; INSERM UMR 952, Physiopathologie des Maladies du Système Nerveux Central, Paris, France., Puget K; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France., Martinez J; Faculté de Pharmacie, Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, France.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2016 Apr; Vol. 173 (8), pp. 1314-28. Date of Electronic Publication: 2016 Mar 08.
DOI: 10.1111/bph.13424
Abstrakt: Background and Purpose: Using an in-house bioinformatics programme, we identified and synthesized a novel nonapeptide, H-Pro-Pro-Thr-Thr-Thr-Lys-Phe-Ala-Ala-OH. Here, we have studied its biological activity, in vitro and in vivo, and have identified its target in the brain.
Experimental Approach: The affinity of the peptide was characterized using purified whole brain and striatal membranes from guinea pigs and rats . Its effect on behaviour in rats following intra-striatal injection of the peptide was investigated. A photoaffinity UV cross-linking approach combined with subsequent affinity purification of the ligand covalently bound to its receptor allowed identification of its target.
Key Results: The peptide bound with high affinity to a single class of binding sites, specifically localized in the striatum and substantia nigra of brains from guinea pigs and rats. When injected within the striatum of rats, the peptide stimulated in vitro and in vivo dopamine release and induced dopamine-like motor effects. We purified the target of the peptide, a ~151 kDa protein that was identified by MS/MS as angiotensin converting enzyme (ACE I). Therefore, we decided to name the peptide acein.
Conclusion and Implications: The synthetic nonapeptide acein interacted with high affinity with brain membrane-bound ACE. This interaction occurs at a different site from the active site involved in the well-known peptidase activity, without modifying the peptidase activity. Acein, in vitro and in vivo, significantly increased stimulated release of dopamine from the brain. These results suggest a more important role for brain ACE than initially suspected.
(© 2016 The British Pharmacological Society.)
Databáze: MEDLINE
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