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The novel nonapeptide acein targets angiotensin converting enzyme in the brain and induces dopamine release
Author(s) -
Neasta Jérémie,
Valmalle Charlène,
Coyne AnneClaire,
Carnazzi Eric,
Subra Gilles,
Galleyrand JeanClaude,
Gagne Didier,
M'Kadmi Céline,
Bernad Nicole,
Bergé Gilbert,
Cantel Sonia,
Marin Philippe,
Marie Jacky,
Banères JeanLouis,
Kemel MarieLou,
Daugé Valérie,
Puget Karine,
Martinez Jean
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13424
Subject(s) - in vivo , dopamine , peptide , striatum , in vitro , chemistry , biochemistry , ligand (biochemistry) , receptor , enzyme , substantia nigra , biology , endocrinology , dopaminergic , microbiology and biotechnology
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.