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Design and biological assessment of membrane-tethering neuroprotective peptides derived from the pituitary adenylate cyclase-activating polypeptide type 1 receptor

Poujol de Molliens, Mathilde; Jamadagni, Priyanka; Létourneau, Myriam; Devost, Dominic; Hébert, Terence E; Patten, Shunmoogum A.; Fournier, Alain; Chatenet, David (2019). Design and biological assessment of membrane-tethering neuroprotective peptides derived from the pituitary adenylate cyclase-activating polypeptide type 1 receptor Biochimica et Biophysica acta , vol. 1863 , nº 11: 129398. p. 1-11. DOI: 10.1016/j.bbagen.2019.07.007.

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Résumé

BACKGROUND: The pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1), a class B G protein-coupled receptor (GPCR), has emerged as a promising target for treating neurodegenerative conditions. Unfortunately, despite years of research, no PAC1-specific agonist has been discovered, as activity on two other GPCRs, VPAC1 and VPAC2, is retained with current analogs. Cell signaling is related to structural modifications in the intracellular loops (ICLs) of GPCRs. Thus, we hypothesized that peptides derived from the ICLs (called pepducins) of PAC1 might initiate, as allosteric ligands, signaling cascades after recognition of the parent receptor and modulation of its conformational landscape.

METHODS: Three pepducins were synthesized and evaluated for their ability to 1) promote cell survival; 2) stimulate various signaling pathways associated with PAC1 activation; 3) modulate selectively PAC1, VPAC1 or VPAC2 activation; and 4) sustain mobility and prevent death of dopaminergic neurons in a zebrafish model of neurodegeneration.

RESULTS: Assays demonstrated that these molecules promote SH-SY5Y cell survival, a human neuroblastoma cell line expressing PAC1, and activate signaling via Gαs and Gαq, with distinct potencies and efficacies. Also, PAC1-Pep1 and PAC1-Pep2 activated selectively PAC1-mediated Gαs stimulation. Finally, experiments, using a zebrafish neurodegeneration model, showed a neuroprotective action with all three pepducins and in particular, revealed the ability of PAC1-Pep1 and PAC1-Pep3 to preserve fish mobility and tyrosine hydroxylase expression in the brain.

CONCLUSION: We have developed the first neuroprotective pepducins derived from PAC1, a class B GPCR.

GENERAL SIGNIFICANCE: PAC1-derived pepducins represent attractive templates for the development of innovative neuroprotecting molecules.

Type de document: Article
Mots-clés libres: BRET-based biosensor; Neuroprotection; PAC1 receptor; PACAP; Parkinson's disease; Pepducin
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 05 févr. 2020 21:58
Dernière modification: 05 févr. 2020 21:58
URI: http://espace.inrs.ca/id/eprint/8557

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