Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic cell

Wataru R. Yamamoto, Robert N. Bone, Paul Sohn, Farooq Syed, Christopher A. Reissaus, Amber L. Mosley, Aruna B. Wijeratne, Jason D. True, Xin Tong, Tatsuyoshi Kono, Carmella Evans-Molina

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Alterations in endoplasmic reticulum (ER) calcium (Ca2) levels diminish insulin secretion and reduce -cell survival in both major forms of diabetes. The mechanisms responsible for ER Ca2 loss in 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 Ca2 imaging techniques in INS-1 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 Ca2 loss under ER and cytokine stress conditions, respectively. However, RyR blockade distinctly prevented -cell death, propagation of the unfolded protein response (UPR), and dysfunctional glucose-induced Ca2 oscillations in tunicamycin-treated INS-1 cells and mouse islets and Akita islets. Monitoring at the single-cell level revealed that ER stress acutely increases the frequency of intracellular Ca2 transients that depend on both ER Ca2 leakage from the RyR and plasma membrane depolarization. Collectively, these findings indicate that RyR dysfunction shapes ER Ca2 dynamics in cells and regulates both UPR activation and cell death, suggesting that RyR-mediated loss of ER Ca2 may be an early pathogenic event in diabetes.

Original languageEnglish (US)
Pages (from-to)168-181
Number of pages14
JournalJournal of Biological Chemistry
Volume294
Issue number1
DOIs
StatePublished - Jan 4 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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