PUBLICATION
Design and biological assessment of membrane-tethering neuroprotective peptides derived from the pituitary adenylate cyclase-activating polypeptide type 1 receptor
- Authors
- de Molliens, M.P., Jamadagni, P., Létourneau, M., Devost, D., Hébert, T.E., Patten, S.A., Fournier, A., Chatenet, D.
- ID
- ZDB-PUB-190716-10
- Date
- 2019
- Source
- Biochimica et biophysica acta. General subjects 1863(11): 129398 (Journal)
- Registered Authors
- Patten, Shumoogum
- Keywords
- BRET-based biosensor, Neuroprotection, PAC1 receptor, PACAP, Parkinson's disease, Pepducin
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Cell Survival/drug effects
- HEK293 Cells
- Humans
- Neurogenesis/drug effects*
- Neuroprotective Agents*/chemistry
- Neuroprotective Agents*/pharmacology
- Peptides*/chemistry
- Peptides*/pharmacology
- Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/chemistry*
- Zebrafish/embryology*
- PubMed
- 31306709 Full text @ BBA General Subjects
Citation
de Molliens, M.P., Jamadagni, P., Létourneau, M., Devost, D., Hébert, T.E., Patten, S.A., Fournier, A., Chatenet, D. (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. General subjects. 1863(11):129398.
Abstract
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 demonstrate that these molecules promoted SH-SY5Y cell survival, a human neuroblastoma cell line expressing PAC1, and activated 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping