Differential roles of beta-cell IP3R and RyR ER Ca2+channels in ER stress-induced alterations of beta-cell Ca2+homeostasis

Abstract

AbstractPancreatic 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 Ca2+. The endoplasmic reticulum (ER) helps regulate beta-cell cytosolic Ca2+, and ER stress can lead to ER Ca2+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 Ca2+dysregulation, INS-1 832/13 cells and primary mouse islets were treated with tunicamycin. This increased RyR1 mRNA and potentiated RyR-mediated Ca2+signaling without affecting RyR2 mRNA. TM treatment also enhanced IP3R function, while it decreased IP3R1 and IP3R3 mRNA. Stress reduced ER Ca2+, triggered oscillations in cytosolic Ca2+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 Ca2+oscillations due to tunicamycin treatment and did not protect beta cells from tunicamycin-induced apoptosis, although xestospongin-C inclusion prevented ER Ca2+depletion. Taken together, changes in RyR1 function were shown to play a critical role in ER stress induced Ca2+dysfunction and beta-cell apoptosis.