The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells

Abstract

The endoplasmic reticulum (ER) mediates the first steps of protein assembly within the secretory pathway and is the site where protein folding and quality control are initiated. The storage and release of Ca2+ are critical physiological functions of the ER. Disrupted ER homeostasis activates the unfolded protein response (UPR), a pathway which attempts to restore cellular equilibrium in the face of ER stress. Unremitting ER stress, and insufficient compensation for it results in beta-cell apoptosis, a process that has been linked to both type 1 diabetes (T1D) and type 2 diabetes (T2D). Both types are characterized by progressive beta-cell failure and a loss of beta-cell mass, although the underlying causes are different. The reduction of mass occurs secondary to apoptosis in the case of T2D, while beta cells undergo autoimmune destruction in T1D. In this review, we examine recent findings that link the UPR pathway and ER Ca2+ to beta cell dysfunction. We also discuss how UPR activation in beta cells favors cell survival versus apoptosis and death, and how ER protein chaperones are involved in regulating ER Ca2+ levels. Abbreviations: BiP, Binding immunoglobulin Protein ER; endoplasmic reticulum; ERAD, ER-associated protein degradation; IFN, interferon; IL, interleukin; JNK, c-Jun N-terminal kinase; KHE, proton-K+ exchanger; MODY, maturity-onset diabetes of young; PERK, PRKR-like ER kinase; SERCA, Sarco/Endoplasmic Reticulum Ca2+-ATPases; T1D, type 1 diabetes; T2D, type 2 diabetes; TNF, tumor necrosis factor; UPR, unfolded protein response; WRS, Wolcott–Rallison syndrome.

Weighted gene co-expression network analysis identifies molecular pathways and hub genes involved in broiler White Striping and Wooden Breast myopathies

“…the preservation of normal Ca 2+ storage and release) could explain the alteration in calcium signaling pathways found by Zambonelli et al 5 . Furthermore, ER dysfunction has important consequences for insulin secretion and glucose metabolism alteration 44 , 45 , which agrees with the modified glycolytic enzymes expression previously found in abnormal breasts 5 . These statements could also explain the severely altered glucose metabolism identified by Lake and Abasht 20 and Baldi et al 46 in broilers affected by WB.…”

“…The ER stress would also explain the dysregulation in calcium homeostasis observed in abnormal breasts, already in 2- and 3-weeks old broilers 20 . In fact, the ER represents a dynamic Ca 2+ store, and failure in ER homeostasis leads to several conditions well described in abnormal breasts, such as dysregulation of calcium homeostasis, UPR activation, and cellular apoptosis 43 , 44 . According to this, our previous results evidenced the up-regulation of genes linked to calcium homeostasis, with particular reference to those involved in processes leading to increased intracellular Ca 2+ (i.e.…”

ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells

“…Disrupted ER homeostasis has been proposed to be a potential cause of T2DM (14) and increasing evidence has emerged suggesting that the ER stress cascade is activated in islets from T2DM patients and from animal models of diabetes (23,29,30). We have recently discussed the potential links between disrupted ER homeostasis and altered beta cell function in a review article (31). Other groups have also proposed the relevance of UPR signaling to beta cell loss and the pathology of diabetes (32).…”

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

“…Similarly, the ER is involved in the biogenesis of lipids and steroid hormones, which are subsequently distributed throughout the cell; CYP activities are essential for these pathways. Moreover, the ER serves as a tightly regulated intracellular calcium store [ 88 ], and regulated calcium release by the ER can be influenced by the presence of ROS. Below we focus on the developing understanding of how fluctuations in H 2 O 2 production at the ER from these various sources are sensed.…”