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

Alterations in endoplasmic reticulum (ER) calcium (Ca) levels diminish insulin secretion and reduce β-cell survival in both major forms of diabetes. The mechanisms responsible for ER Ca loss in β cells remain incompletely understood. Moreover, a specific role for either ryanodine receptor (RyR) or inositol 1,4,5-triphosphate receptor (IPR) dysfunction in the pathophysiology of diabetes remains largely untested. To this end, here we applied intracellular and ER Ca imaging techniques in INS-1 β cells and isolated islets to determine whether diabetogenic stressors alter RyR or IPR function. Our results revealed that the RyR is sensitive mainly to ER stress-induced dysfunction, whereas cytokine stress specifically alters IPR activity. Consistent with this observation, pharmacological inhibition of the RyR with ryanodine and inhibition of the IPR with xestospongin C prevented ER Ca loss under ER and cytokine stress conditions, respectively. However, RyR blockade distinctly prevented β-cell death, propagation of the unfolded protein response (UPR), and dysfunctional glucose-induced Ca oscillations in tunicamycin-treated INS-1 β cells and mouse islets and Akita islets. Monitoring at the single-cell level revealed that ER stress acutely increases the frequency of intracellular Ca transients that depend on both ER Ca leakage from the RyR and plasma membrane depolarization. Collectively, these findings indicate that RyR dysfunction shapes ER Ca dynamics in β cells and regulates both UPR activation and cell death, suggesting that RyR-mediated loss of ER Ca may be an early pathogenic event in diabetes.