Skip to main content
eScholarship
Open Access Publications from the University of California

UCSF

UC San Francisco Previously Published Works bannerUCSF

Nicotinic acetylcholine receptor signaling regulates inositol-requiring enzyme 1α activation to protect β-cells against terminal unfolded protein response under irremediable endoplasmic reticulum stress.

  • Author(s): Ishibashi, Tatsuya
  • Morita, Shuhei
  • Kishimoto, Shohei
  • Uraki, Shinsuke
  • Takeshima, Ken
  • Furukawa, Yasushi
  • Inaba, Hidefumi
  • Ariyasu, Hiroyuki
  • Iwakura, Hiroshi
  • Furuta, Hiroto
  • Nishi, Masahiro
  • Papa, Feroz R
  • Akamizu, Takashi
  • et al.

Published Web Location

https://doi.org/10.1111/jdi.13211
Abstract

Aims/introduction

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.

Materials and methods

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.

Results

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.

Conclusions

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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
Current View