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

Aims/Introduction Under irremediable endoplasmic reticulum (ER) stress, hyperactivated inositol-requiring enzyme 1 alpha (IRE1 alpha) triggers the terminal unfolded protein response (T-UPR), causing crucial cell dysfunction and apoptosis. We hypothesized that nicotinic acetylcholine receptor (nAChR) signaling regulates IRE1 alpha activation to protect beta-cells from the T-UPR under ER stress. Materials and Methods The effects of nicotine on IRE1 alpha 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-beta H1 beta-cell lines. Doxycycline-inducible IRE1 alpha overexpression or ER stress agents were used to induce IRE1 alpha activation. An alpha 7 subunit-specific nAChR agonist (PNU-282987) and small interfering ribonucleic acid for alpha 7 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 IRE1 alpha hyperactivation or ER stress agents. Nicotine attenuated X-box-binding protein-1 messenger ribonucleic acid site-specific splicing and IRE1 alpha autophosphorylation induced by ER stress. Furthermore, PNU-282987 attenuated T-UPR induction by either forced IRE1 alpha 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 alpha 7 nAChR. Finally, nicotine suppressed apoptosis induced by either forced IRE1 alpha activation or ER stress agents. Conclusions Our findings suggest that nAChR signaling regulates IRE1 alpha activation to protect beta-cells from the T-UPR and apoptosis under ER stress partly through alpha 7 nAChR. Targeting nAChR signaling to inhibit the T-UPR cascade may therefore hold therapeutic promise by thwarting beta-cell death in diabetes.