β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation

Gupta, Dhananjay; Lacayo, Adam A.; Greene, Shane M.; Leahy, J.L.; Jetton, Thomas L.

doi:10.1074/jbc.ra118.004617

Cited by 25 publications

(25 citation statements)

References 45 publications

(70 reference statements)

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“…One of the reasons for the conflicting observations of the effect of nicotine on UPR might be related to the tissue specificity of the effect of nicotine. In β‐cells, previous studies showed the expressions of the α7 subunit in rat islet β‐cells, and the α2, α3, α4, α7 and β2 subunits in INS‐1 cells. We also preliminarily confirmed the expression of the α2, α5 and β2 subunits, as well as the α7 subunit (Figure ; Table ).…”

Section: Discussionsupporting

confidence: 77%

“…It has also been shown that nicotine or the systemic increase in ACh levels ameliorates the diabetic phenotypes by stimulating the Th1 to Th2 cytokine switch or pancreatic T‐cell differentiation in NOD mice and multiple low‐dose streptozotocin mice. In addition, the specific stimulation of nAChR α7 has recently been shown to activate anti‐inflammatory and prosurvival pathways in cytokine‐treated INS‐1 cells and murine islets. In contrast, we and other groups have recently shown that UPR markers are induced in β‐cells from type 1 diabetes patients and NOD mice, and that established diabetes in NOD mice could be reversed by KIRA.…”

Section: Discussionmentioning

confidence: 80%

“…Furthermore, we showed that the monoselective IRE1α inhibitor KIRA8 rescues β‐cells from T‐UPR and ultimate apoptosis to ameliorate or reverse diabetes in Akita or NOD mice, as shown by the observation that KIRA spares cell survival A‐UPR, but shuts down T‐UPR, showing the essential role of tuning IRE1α output for glucose metabolism in vivo . In contrast, recent reports have emphasized the protective role of global and α7 subunit‐specific nAChR signaling against apoptosis in rodent β‐cells, but the underlying mechanisms are still unknown. These backgrounds encouraged us to investigate the link between nAChR signaling and IRE1α signaling.…”

Section: Discussionmentioning

confidence: 87%

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

Ishibashi

Morita

Kishimoto

et al. 2020

J of Diabetes Invest

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Aims/Introduction: Under irremediable endoplasmic reticulum (ER) stress, hyperactivated inositol-requiring enzyme 1a (IRE1a) triggers the terminal unfolded protein response (T-UPR), causing crucial cell dysfunction and apoptosis. We hypothesized that nicotinic acetylcholine receptor (nAChR) signaling regulates IRE1a activation to protect b-cells from the T-UPR under ER stress. Materials and Methods: The effects of nicotine on IRE1a 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-bH1 b-cell lines. Doxycycline-inducible IRE1a overexpression or ER stress agents were used to induce IRE1a activation. An a7 subunit-specific nAChR agonist (PNU-282987) and small interfering ribonucleic acid for a7 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 IRE1a hyperactivation or ER stress agents. Nicotine attenuated X-box-binding protein-1 messenger ribonucleic acid site-specific splicing and IRE1a autophosphorylation induced by ER stress. Furthermore, PNU-282987 attenuated T-UPR induction by either forced IRE1a 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 a7 nAChR. Finally, nicotine suppressed apoptosis induced by either forced IRE1a activation or ER stress agents. Conclusions: Our findings suggest that nAChR signaling regulates IRE1a activation to protect b-cells from the T-UPR and apoptosis under ER stress partly through a7 nAChR. Targeting nAChR signaling to inhibit the T-UPR cascade may therefore hold therapeutic promise by thwarting b-cell death in diabetes. homeostasis during both constitutive secretory protein folding and assembly, and under conditions of excessive protein folding demand (i.e., ER stress) 1. Under ER stress, intracellular signaling pathways termed the unfolded protein response (UPR)

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 87%

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

Ishibashi

Morita

Kishimoto

et al. 2020

J of Diabetes Invest

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“…Previously, we showed that the brain α7 and α4β2 nAChRs could be restored if LPS-treated mice were injected with mesenchymal stem cells (MSCs) or their conditioned medium (Lykhmus et al, 2019a). The α7 nAChRs are known to mediate pro-survival signaling (Smedlund et al, 2011;Gupta et al, 2018); therefore, their activation could in some way resemble the effect of the growth/trophic factors produced by MSCs.…”

Section: Discussionmentioning

confidence: 99%

Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice

Lykhmus

Kalashnyk

Uspenska

et al. 2020

Front. Aging Neurosci.

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Neuroinflammation accompanies or even precedes the development of cognitive changes in many brain pathologies, including Alzheimer's disease. Therefore, dampening inflammatory reactions within the brain is a promising strategy for supporting cognitive functions in elderly people and for preventing the development of neurodegenerative disorders. Nicotinic acetylcholine receptors containing α7 subunits (α7 nAChRs) are involved in regulating cell survival, inflammation, and memory. The aim of our study was to evaluate the efficiency of α7-specific therapy at different stages of inflammation and to compare the effects of orthosteric agonist PNU282987 and type 2 positive allosteric modulator (PAM) PNU120596 in mice after a single injection of lipopolysaccharide (LPS). The data presented demonstrate that PNU282987 protected mice from LPS-induced impairment of episodic memory by decreasing IL-6 levels in the blood, stabilizing the brain mitochondria and up-regulating the brain α7-, α3-, and α4-containing nAChRs. Such treatment was efficient when given simultaneously with LPS or a week after LPS injection and was not efficient if LPS had been injected 2 months before. PNU120596 also decreased IL-6, stabilized mitochondria and up-regulated the brain nAChRs. However, its memory-improving effect was transient and disappeared after the end of the injection cycle. Moreover, cessation of PNU120596 treatment resulted in a sharp increase in IL-1β and IL-6 levels in the blood. It is concluded that activating α7 nAChRs protects the mouse brain from the pathogenic effect of LPS in the early stages of inflammation but is not efficient when irreversible changes have already occurred. The use of a PAM does not improve the effect of the agonist, possibly potentiates the effect of endogenous agonists, and results in undesirable effects after treatment cessation.

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“…We thus postulate that cynandione A stimulates β-endorphin expression through autocrime IL-10 expression via the STAT3 signaling. Activation of α7 nAChRs indeed led to reducing in ammatory drive through a JAK2-STAT3 pathway that couples with CREB/Irs2/Akt survival signaling in the mouse islets [73]. α7 nAChR activation increased hypothalamic POMC expression by triggering JAK2/STAT3 pathway [74].…”

Section: Cynandione a Stimulated Il-10 And β-Endorphin Expression In mentioning

confidence: 99%

Cynandione A alleviates neuropathic pain through spinal microglial interleukin-10/β-endorphin expression following α7 nicotinic acetylcholine receptor activation

Han

Yin

Wang

et al. 2020

Preprint

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Abstract Background Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antihypersensitivity effects in neuropathic pain. This study sought to explore the target molecule and mechanisms underlying cynandione A mechanical antiallodynia, particularly related to the spinal glial expression of IL-10/β-endorphin, cAMP/PKA/p38/CREB signaling and α7 nicotinic acetylcholine receptor (α7 nAChR) activation. Methods IL-10 and β-endorphin in the spinal cord of spinal nerve ligation-induced neuropathic pain rats and cultured primary microglia were assessed by qRT-PCR and ELISA assays. Double immunofluorescence staining of IL-10, β-endorphin with glial and neuronal cellular biomarkers was also conducted in the spinal cord and cultured primary microglia. Microglial phosphorylation of PKA, p38, CREB and STAT3 were detected using western blot. Results Cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased IL-10 and β-endorphin (but not dynorphin A) expression in the spinal cords and cultured primary microglia. The IL-10 antibody attenuated cynandione A-induced spinal or microglial gene expression of β-endorphin and mechanical antiallodynia, whereas the β-endorphin antiserum blocked cynandione A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly declined cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated microglial phosphorylation of PKA, p38 and CREB, which was inhibited by methyllycaconitine. Treatment with the adenylyl cyclase inhibitor DDA, PKA inhibitor H-89, p38 inhibitor SB203580 and CREB inhibitor KG501 attenuated cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, H-89 and the IL-10 antibody. The STAT3 inhibitor NSC74859 weakened cynandione A-induced mechanical antiallodynia and spinal expression of β-endorphin. Conclusion Our results illustrate that cynandione A produces mechanical antiallodynia through spinal microglial expression of IL-10 via the cAMP/PKA/p38/CREB signaling and subsequent β-endorphin expression via the IL-10/STAT3 signaling, following α7 nAChR activation.

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β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation

Cited by 25 publications

References 45 publications

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

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

Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice

Cynandione A alleviates neuropathic pain through spinal microglial interleukin-10/β-endorphin expression following α7 nicotinic acetylcholine receptor activation

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