Resveratrol inhibits phorbol ester-induced membrane translocation of presynaptic Munc13-1.
Biochim Biophys Acta Gen Subj
; 1861(11 Pt A): 2640-2651, 2017 Nov.
Article
in En
| MEDLINE
| ID: mdl-28713022
ABSTRACT
BACKGROUND:
Resveratrol (1) is a naturally occurring polyphenol that has been implicated in neuroprotection. One of resveratrol's several biological targets is Ca2+-sensitive protein kinase C alpha (PKCα). Resveratrol inhibits PKCα by binding to its activator-binding C1 domain. Munc13-1 is a C1 domain-containing Ca2+-sensitive SNARE complex protein essential for vesicle priming and neurotransmitter release.METHODS:
To test if resveratrol could also bind and inhibit Munc13-1, we studied the interaction of resveratrol and its derivatives, (E)-1,3-dimethoxy-5-(4-methoxystyryl)benzene, (E)-5,5'-(ethene-1,2-diyl)bis(benzene-1,2,3-triol), (E)-1,2-bis(3,4,5-trimethoxyphenyl)ethane, and (E)-5-(4-(hexadecyloxy)-3,5-dihydroxystyryl)benzene-1,2,3-triol with Munc13-1 by studying its membrane translocation from cytosol to plasma membrane in HT22 cells and primary hippocampal neurons.RESULTS:
Resveratrol, but not the derivatives inhibited phorbol ester-induced Munc13-1 translocation from cytosol to membrane in HT22 cells and primary hippocampal neurons, as evidenced by immunoblot analysis and confocal microscopy. Resveratrol did not show any effect on Munc13-1H567K, a mutant which is not sensitive to phorbol ester. Binding studies with Munc13-1 C1 indicated that resveratrol competes with phorbol ester for the binding site. Molecular docking and dynamics studies suggested that hydroxyl groups of resveratrol interact with phorbol-ester binding residues in the binding pocket. CONCLUSIONS ANDSIGNIFICANCE:
This study characterizes Munc13-1 as a target of resveratrol and highlights the importance of dietary polyphenol in the management of neurodegenerative diseases.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stilbenes
/
SNARE Proteins
/
Nerve Tissue Proteins
/
Neurons
Limits:
Animals
/
Humans
Language:
En
Journal:
Biochim Biophys Acta Gen Subj
Year:
2017
Type:
Article
Affiliation country:
United States