Abstract
Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. In this study, we aimed to investigate the effect of CaBP-9k on cell survival in pancreatic beta cells. Six-month-old wildtype CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice were used to compare the pathological phenotypes of calcium-binding protein-deleted mice. Subsequently, the endoplasmic reticulum (ER) stress reducer tauroursodeoxycholic acid (TUDCA) was administered to wildtype and CaBP-9k KO mice. In vitro assessment of the role of CaBP-9k was performed following CaBP-9k overexpression and treatment with the ER stress inducer thapsigargin. Six-month-old CaBP-9k KO mice showed reduced islet volume and up-regulation of cell death markers resulting from ER stress, which led to pancreatic beta cell death. TUDCA treatment recovered islet volume, serum insulin level, and abdominal fat storage by CaBP-9k ablation. CaBP-9k overexpression elevated insulin secretion and recovered thapsigargin-induced ER stress in the INS-1E cell line. The results of this study show that CaBP-9k can protect pancreatic beta cell survival from ER stress and contribute to glucose homeostasis, which can reduce the risk of type 1 diabetes and provide the molecular basis for calcium supplementation to diabetic patients.
Highlights
Calbindin-D9k (CaBP-9k) is a 9-kDa polypeptide containing two EF-calcium-binding sites, which are usually expressed in the intestine, kidney, uterus, and pituitary gland
Intracellular free calcium ion and endoplasmic reticulum (ER) calcium ion levels are modulated by several calcium channels, including the sarcoplasmic reticulum calcium ion ATPase (SERCA) 2a and 2b, inositol 1,4,5-trisphosphate receptor (IP3R), and ryanodine receptor 2 (RyR2)
The insulin level was reduced (Figure 1E), and urinary glucose (Figure 1F) and water consumption (Figure 1G) were elevated, to diabetic symptoms in CaBP-9k-deleted compared to WT mice
Summary
Calbindin-D9k (CaBP-9k) is a 9-kDa polypeptide containing two EF-calcium-binding sites, which are usually expressed in the intestine, kidney, uterus, and pituitary gland. CaBP-9k regulates the amount of intracellular calcium in order to prevent cell death caused by toxic free calcium levels [2]. The intracellular calcium ion concentration is regulated via the endoplasmic reticulum (ER)-mediated pathway, in which calcium ions move across the ER membrane via calcium channels and pumps [3]. Intracellular free calcium ion and ER calcium ion levels are modulated by several calcium channels, including the sarcoplasmic reticulum calcium ion ATPase (SERCA) 2a and 2b, inositol 1,4,5-trisphosphate receptor (IP3R), and ryanodine receptor 2 (RyR2). Disruption of intracellular calcium ion homeostasis can trigger ER stress [5]. Dysregulation of the intracellular calcium ion level can result in the activation of apoptotic pathways [8,9]
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