A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element‐binding protein/ and Growth Arrest And DNA‐Damage‐Inducible 34/ eukaryotic Initiation Factor 2α pathways

Abstract

Endoplasmic reticulum (ER) stress is one of the main molecular events underlying pancreatic beta cell (PBC) failure, apoptosis, and a decrease in insulin secretion. Recent studies have highlighted the fundamental role of A2a adenosine receptor (A2aR) in potentiation of insulin secretion and proliferation of PBCs. However, possible protective effects of A2aR signaling against ER stress have not been elucidated yet. Thus, in the present study, we aimed to investigate the effects of A2aR activation in MIN6 beta cells undergoing tunicamycin (TM)‐mediated ER stress. A2aR expression and activity were evaluated using real‐time polymerase chain reaction and measurement of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho‐protein kinase B or Akt (p‐Akt)/Akt, and phospho‐Cyclic adenosine monophosphate response element‐binding protein/CREB levels in response to a specific agonist (CGS 21680). Survival and proliferation in TM and CGS 21680 cotreated cells were evaluated using 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), annexin V–fluorescein isothiocyanate (FITC)/propidium iodide staining, colony formation, and 5‐bromo‐2′‐deoxyuridine (Brdu) assays. In addition, the effects of A2aR stimulation on insulin secretion were evaluated using the enzyme‐linked immunosorbent assay. B‐cell lymphoma 2 (Bcl‐2), phospho‐eukaryotic Initiation Factor 2α (p‐eIF2α)/eIF2α, growth arrest and DNA‐damage‐inducible 34 (GADD34), X‐box binding protein 1 (XBP‐1), spliced X‐box binding protein 1 (XBP‐1s), immunoglobulin heavy‐chain‐binding protein (BIP), and CCAAT‐enhancer‐binding protein homologous protein (CHOP) levels were evaluated using western blotting. Our results showed a decrease in A2aR expression and p‐Akt/Akt and p‐CREB/CREB levels in TM‐pretreated cells. We also mentioned that CGS 21680 effectively increased cell survival, proliferation, and insulin secretion in TM‐treated cells. The antiapoptotic effects were possibly mediated through Bcl‐2 upregulation. Our western blotting results indicated that A2aR effectively downregulated p‐eIF2α/eIF2α, XBP‐1, XBP‐1s, BIP, and CHOP levels, whereas GADD34 was upregulated. Altogether, the present study revealed that A2aR signaling through PKA/Akt/CREB mediators alleviated TM cytotoxicity effects in MIN6 beta cells. Thus, the stimulation of this receptor was seen as a new approach to control ER stress in the PBC cells.

USP15 Enhances Re-epithelialization Through Deubiquitinating EIF4A1 During Cutaneous Wound Repair

“…These factors have been proven to play a vital role in wound healing, tumorigenesis, cell stemness and epithelial-mesenchymal transition, etc. For example, elF2a is involved in DNA damage repair and could regulate autophagy in tumors ( Arasi et al, 2019 ). elF3 family modulate of the hypoxia inducible factors (HIFs) and suppress tumorigenesis.…”

Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation

“…Although endogenous adenosine is accumulated during ischemia and is known to be an important mediator in innate protective pathways triggered by ischemic events, the effect of direct adenosine administration is limited by its short half-life and the simultaneous stimulation of all four adenosine receptor subtypes (A1, A 2a, A 2b , A3) [ 27 , 52 ]. Despite a significant overlap in the function of the receptors, most reports suggest that cAMP- and PKA-mediated protective and anti-inflammatory and anti-apoptotic effects are predominantly associated with the activation of the A 2a receptors [ 17 , 22 , 53 ], which underlines the importance of using a rather selective receptor stimulation. Previous molecular biological studies confirmed that the physiological and/or artificial stimulation of the adenosine A2a receptors induces the sequential activation of adenylate cyclase and protein kinase A (PKA) [ 53 , 54 ].…”

“…Despite a significant overlap in the function of the receptors, most reports suggest that cAMP- and PKA-mediated protective and anti-inflammatory and anti-apoptotic effects are predominantly associated with the activation of the A 2a receptors [ 17 , 22 , 53 ], which underlines the importance of using a rather selective receptor stimulation. Previous molecular biological studies confirmed that the physiological and/or artificial stimulation of the adenosine A2a receptors induces the sequential activation of adenylate cyclase and protein kinase A (PKA) [ 53 , 54 ]. The latter, by phosphorylating the adenosine A2a receptor, allows the G protein-mediated activation of phosphatidylinositol 3-kinase (PI3K).…”

“…The latter, by phosphorylating the adenosine A2a receptor, allows the G protein-mediated activation of phosphatidylinositol 3-kinase (PI3K). In turn, PI3K inhibits necrotic and apoptotic cell death via PDK-1/PKC/p38-MAPK- and PDK-1/Akt/BAD-mediated downstream pathways, respectively [ 53 , 54 ]. Therefore, we have measured the activity ratio of PKA in serum samples following OLT with and without adenosine A2a receptor stimulation.…”

The Effects of Meditation with a Biofeedback Program on Stress and Depression Levels among People with Mild Depression Diabetes

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