Nicotinic acetylcholine receptor signaling regulates inositol-requiring enzyme 1α activation to protect β-cells against terminal unfolded protein response under irremediable endoplasmic reticulum stress.
Animals
Apoptosis
/ physiology
Cell Line
Endoplasmic Reticulum Stress
/ physiology
Endoribonucleases
/ metabolism
Humans
Insulin-Secreting Cells
/ metabolism
Protective Agents
/ pharmacology
Protein Serine-Threonine Kinases
/ metabolism
Rats
Receptors, Nicotinic
/ metabolism
Signal Transduction
/ physiology
Unfolded Protein Response
/ physiology
Inositol-requiring enzyme 1α
Nicotinic acetylcholine receptor
Pancreatic β cell
Journal
Journal of diabetes investigation
ISSN: 2040-1124
Titre abrégé: J Diabetes Investig
Pays: Japan
ID NLM: 101520702
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
received:
20
09
2019
revised:
22
12
2019
accepted:
05
01
2020
pubmed:
12
1
2020
medline:
7
7
2021
entrez:
12
1
2020
Statut:
ppublish
Résumé
Under irremediable endoplasmic reticulum (ER) stress, hyperactivated inositol-requiring enzyme 1α (IRE1α) triggers the terminal unfolded protein response (T-UPR), causing crucial cell dysfunction and apoptosis. We hypothesized that nicotinic acetylcholine receptor (nAChR) signaling regulates IRE1α activation to protect β-cells from the T-UPR under ER stress. The effects of nicotine on IRE1α activation and key T-UPR markers, thioredoxin-interacting protein and insulin/proinsulin, were analyzed by real-time polymerase chain reaction and western blotting in rat INS-1 and human EndoC-βH1 β-cell lines. Doxycycline-inducible IRE1α overexpression or ER stress agents were used to induce IRE1α activation. An α7 subunit-specific nAChR agonist (PNU-282987) and small interfering ribonucleic acid for α7 subunit-specific nAChR were used to modulate nAChR signaling. Nicotine inhibits the increase in thioredoxin-interacting protein and the decrease in insulin 1/proinsulin expression levels induced by either forced IRE1α hyperactivation or ER stress agents. Nicotine attenuated X-box-binding protein-1 messenger ribonucleic acid site-specific splicing and IRE1α autophosphorylation induced by ER stress. Furthermore, PNU-282987 attenuated T-UPR induction by either forced IRE1α activation or ER stress agents. The effects of nicotine on attenuating thioredoxin-interacting protein and preserving insulin 1 expression levels were attenuated by pharmacological and genetic inhibition of α7 nAChR. Finally, nicotine suppressed apoptosis induced by either forced IRE1α activation or ER stress agents. Our findings suggest that nAChR signaling regulates IRE1α activation to protect β-cells from the T-UPR and apoptosis under ER stress partly through α7 nAChR. Targeting nAChR signaling to inhibit the T-UPR cascade may therefore hold therapeutic promise by thwarting β-cell death in diabetes.
Identifiants
pubmed: 31925927
doi: 10.1111/jdi.13211
pmc: PMC7378412
doi:
Substances chimiques
Protective Agents
0
Receptors, Nicotinic
0
ERN1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
801-813Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP17H07033
Organisme : Japan Society for the Promotion of Science
ID : JP18K16242
Organisme : Smoking Research Foundation
ID : (T.A, H.A)
Organisme : Japan Diabetes Foundation
ID : (S.M)
Informations de copyright
© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.
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