Differential roles of beta-cell IP3R and RyR ER Ca ²⁺ channels in ER stress-induced alterations of beta-cell Ca ²⁺ homeostasis

This is the authors' abstract. We don't add key points for this paper.

Pancreatic beta cells maintain glucose homeostasis by secreting pulses of insulin in response to a rise in glucose. Pulsatile secretion occurs due to glucose-induced oscillations in beta-cell cytosolic Ca 2+ . The endoplasmic reticulum (ER) helps regulate beta-cell cytosolic Ca 2+ , and ER stress can lead to ER Ca 2+ depletion, beta-cell dysfunction and an increased risk of type 2 diabetes. To determine the effects of tunicamycin-induced ER stress on ER inositol 1,4,5-triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) and their involvement in subsequent Ca 2+ dysregulation, INS-1 832/13 cells and primary mouse islets were treated with tunicamycin. This increased RyR1 mRNA and potentiated RyR-mediated Ca 2+ signaling without affecting RyR2 mRNA. TM treatment also enhanced IP3R function, while it decreased IP3R1 and IP3R3 mRNA. Stress reduced ER Ca 2+ , triggered oscillations in cytosolic Ca 2+ under subthreshold glucose conditions, and increased apoptosis; these changes were prevented by cotreatment with the RyR1 inhibitor dantrolene. In contrast, inhibiting IP3Rs with xestospongin-C failed to suppress the cytosolic Ca 2+ oscillations due to tunicamycin treatment and did not protect beta cells from tunicamycin-induced apoptosis, although xestospongin-C inclusion prevented ER Ca 2+ depletion. Taken together, changes in RyR1 function were shown to play a critical role in ER stress induced Ca 2+ dysfunction and beta-cell apoptosis.