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bioRxiv · 10.1101/2022.10.11.511769

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

Zhang, I. X.·Hermann, A.·Leon, J.·Arunagiri, A.·Arvan, P.·Satin, L.
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Abstract

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 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.

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Zhang, I. X., Hermann, A., Leon, J., Arunagiri, A., Arvan, P., Satin, L.. 2022-10-11. Differential roles of beta-cell IP3R and RyR ER Ca2+ channels in ER stress-induced alterations of beta-cell Ca2+ homeostasis. https://doi.org/10.1101/2022.10.11.511769

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