First Author | Yamamoto WR | Year | 2019 |
Journal | J Biol Chem | Volume | 294 |
Issue | 1 | Pages | 168-181 |
PubMed ID | 30420428 | Mgi Jnum | J:274728 |
Mgi Id | MGI:6294235 | Doi | 10.1074/jbc.RA118.005683 |
Citation | Yamamoto WR, et al. (2019) Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell. J Biol Chem 294(1):168-181 |
abstractText | Alterations in endoplasmic reticulum (ER) calcium (Ca(2+)) levels diminish insulin secretion and reduce beta-cell survival in both major forms of diabetes. The mechanisms responsible for ER Ca(2+) loss in beta cells remain incompletely understood. Moreover, a specific role for either ryanodine receptor (RyR) or inositol 1,4,5-triphosphate receptor (IP3R) dysfunction in the pathophysiology of diabetes remains largely untested. To this end, here we applied intracellular and ER Ca(2+) imaging techniques in INS-1 beta cells and isolated islets to determine whether diabetogenic stressors alter RyR or IP3R function. Our results revealed that the RyR is sensitive mainly to ER stress-induced dysfunction, whereas cytokine stress specifically alters IP3R activity. Consistent with this observation, pharmacological inhibition of the RyR with ryanodine and inhibition of the IP3R with xestospongin C prevented ER Ca(2+) loss under ER and cytokine stress conditions, respectively. However, RyR blockade distinctly prevented beta-cell death, propagation of the unfolded protein response (UPR), and dysfunctional glucose-induced Ca(2+) oscillations in tunicamycin-treated INS-1 beta cells and mouse islets and Akita islets. Monitoring at the single-cell level revealed that ER stress acutely increases the frequency of intracellular Ca(2+) transients that depend on both ER Ca(2+) leakage from the RyR and plasma membrane depolarization. Collectively, these findings indicate that RyR dysfunction shapes ER Ca(2+) dynamics in beta cells and regulates both UPR activation and cell death, suggesting that RyR-mediated loss of ER Ca(2+) may be an early pathogenic event in diabetes. |