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

Jérémie Neasta (1) , Charlène Valmalle (1) , Anne‐claire Coyne (2) , Eric Carnazzi (1) , Gilles Subra (1) , Jean‐claude Galleyrand (1) , Didier Gagne (1) , Céline M'Kadmi (1) , Nicole Bernad (1) , Gilbert Berge (1) , Sonia Cantel (1) , Philippe Marin (3) , Jacky Marie (1) , Jean‐louis Baneres (1) , Marie‐lou Kemel (4) , Valerie Dauge (2) , Karine Puget (1) , Jean Martinez (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 Physiopathologie des Maladies du Système Nerveux Central
3 IGF - Institut de Génomique Fonctionnelle
4 CIRB - Centre interdisciplinaire de recherche en biologie

Background and PurposeUsing 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 ApproachThe 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 ResultsThe 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 similar to 151kDa protein that was identified by MS/MS as angiotensin converting enzyme (ACE I). Therefore, we decided to name the peptide acein. Conclusion and ImplicationsThe 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.

Mots clés: growth-hormone; alzheimers-disease; concise guide; striatum

Mots clés: nucleus-accumbens; rats; system; receptors; pharmacology; peptide

Domaines: Sciences du Vivant [q-bio]

Jérémie Neasta, Charlène Valmalle, Anne‐claire Coyne, Eric Carnazzi, Gilles Subra, et al.. The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release. British Journal of Pharmacology, 2016, 173 (8), pp.1314--28. ⟨10.1111/bph.13424⟩. ⟨hal-01942451⟩