230-LB: Differential Roles of Beta-Cell IP3R and RyR ER Ca2+ Channels in Tunicamycin-Induced Disruption of Beta-Cell Ca2+ Homeostasis
| العنوان: | 230-LB: Differential Roles of Beta-Cell IP3R and RyR ER Ca2+ Channels in Tunicamycin-Induced Disruption of Beta-Cell Ca2+ Homeostasis |
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| المؤلفون: | Vishal S. Parekh, Juan J. Leon, Leslie S. Satin, Irina Zhang |
| المصدر: | Diabetes. 70 |
| بيانات النشر: | American Diabetes Association, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Chemistry, Ryanodine receptor, Endocrinology, Diabetes and Metabolism, Endoplasmic reticulum, Pancreatic islets, Tunicamycin, Cell biology, chemistry.chemical_compound, medicine.anatomical_structure, Internal Medicine, Unfolded protein response, medicine, Glucose homeostasis, Beta cell, Homeostasis |
| الوصف: | Pancreatic beta cells maintain glucose homeostasis by secreting insulin following a rise in plasma glucose. Insulin secretion is pulsatile, which is brought about because of oscillations in the concentrations of beta-cell cytosolic Ca2+. The endoplasmic reticulum (ER) helps to regulate the cytosolic Ca2+ level, thereby playing a role in Ca2+-induced insulin release. ER stress, triggered by the accumulation of unfolded proteins in the ER, can lead to the ER Ca2+ depletion, which in turn can contribute to beta-cell deterioration and an increased risk of type-2 diabetes. We sought to determine the effects of tunicamycin (TM)-induced ER stress on ER Ca2+ channels, inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyRs), and subsequent alterations in beta-cell Ca2+ homeostasis that result from these alterations. To determine the roles of these receptors in TM-induced beta-cell dysfunction, we treated mouse pancreatic islets with the RyR1 inhibitor dantrolene (Dan) or the IP3R inhibitor xestospongin C (XeC) along with TM. Beta cells treated with TM exhibited altered cytosolic and mitochondrial Ca2+ when in sub-threshold glucose compared to vehicle controls. As TM treatment also reduced ER Ca2+, this raised the possibility that the mitochondrial and cytosolic Ca2+ oscillations seen in stressed cells resulted from increased ER Ca2+ efflux mediated by RyRs and/or IP3Rs. We found that TM-induced ER Ca2+ depletion, as well as cytosolic and mitochondrial Ca2+ oscillations were inhibited by co-treatment with Dan, whereas the inclusion of XeC had little or no effect. Taken together, these results suggest that RyRs, and more specifically RyR1 plays a critical role in mediating the disturbed cellular Ca2+ homeostasis seen in response to the induction of ER stress. Disclosure I. Zhang: None. V. S. Parekh: None. J. J. Leon: None. L. S. Satin: None. Funding National Institutes of Health (R01DK46409); University of Michigan; JDRF (2-SRA-2018-539-A-B) |
| تدمد: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db21-230-lb |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::b54cadd1c268df5dc5ad317e11102ead https://doi.org/10.2337/db21-230-lb |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi...........b54cadd1c268df5dc5ad317e11102ead |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1939327X 00121797 |
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| DOI: | 10.2337/db21-230-lb |