Calbindin-D28k Controls [Ca2+] and Insulin Release

Abstract

Calbindin-D 28k is a 28,000 M r calcium-binding protein initially identified in avian intestine and was the first known target of vitamin D action (1). Calbindin has since been reported in many other tissues including kidney and bone and in tissues that are not primary regulators of serum calcium such as brain and pancreas (2-4). This calcium-binding protein has been conserved during evolution and is regulated by a number of different hormones and factors (3, 4). Calbindin-D 28k , a predominantly cytosolic protein, is a member of a family of high affinity calcium-binding proteins that includes calmodulin, S100 protein, and parvalbumin (5). It has been suggested that the role of calbindin in kidney and intestine is to facilitate transcellular calcium diffusion (6, 7). In brain, calbindin is not vitamin D-dependent and its proposed function is to buffer calcium, resulting in protection against calcium-mediated neurotoxicity (8, 9). In 1979 the discovery in the pancreas of a high affinity receptor for the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), was the first demonstration of a nonclassical target tissue to contain vitamin D receptors (10). Further autoradiographic and immunohistochemical analyses have shown that vitamin D receptors and calbindin-D 28k are both localized in the ␤ cell (11-13). Although these studies and others (14 -17) established a link between the pancreatic ␤ cell and the vitamin D endocrine system and although the importance of calcium in insulin secretion is well known, there is still little information available concerning the exact mechanism whereby vitamin D may affect ␤ cell function. It has been suggested that the role of vitamin D in calcium metabolism of the ␤ cell may involve a genomic effect of 1,25-(OH) 2 D 3 , including the production of calbindin.Although isolated islets and perfused pancreas from vitamin D-deficient animals have previously been used to study the effects of 1,25-(OH) 2 D 3 on ␤ cell function (14 -17), recently we reported that the ␤ cell line R1N1046-38 contains both calbindin and receptors for 1,25-(OH) 2 D 3 and suggested that ␤ cell lines may provide a useful in vitro system for studying the effects of the vitamin D endocrine system on ␤ cell function (18,19). Although interesting data have been generated in numerous studies using RIN cells, the RIN cell line may not be the best model because these cells have little or no response to glucose and the insulin content of these cells is only approximately 0.1% of the insulin content found in the normal ␤ cell.In this study, to understand the role of calbindin-D 28k in the pancreatic ␤ cells, calbindin was transfected and overexpressed in ␤HC and ␤TC cells, pancreatic ␤ cells that secrete insulin in a regulated manner and at levels more comparable with those of normal ␤ cells. Both cell lines are derived from transgenic mice that express the SV40 T-antigen in ␤ cells under the

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

“…Thus, renal failure as the cause of failure to thrive and early death can largely be excluded. Impaired insulin secretion with reduced insulin mRNA expression has been reported in VDR(Ϫ/Ϫ) mice (35), whereas a greater stimulation of insulin secretion by KCl has been reported in CaBP-D28k(Ϫ/Ϫ) mice (36). We found that pancreatic insulin mRNA levels in the double KO mice are normal in comparison with WT mice (data not shown), which rules out insulin as the cause.…”

Gene expression profiling in human insulinoma tissue: genes involved in the insulin secretion pathway and cloning of novel full-length cDNAs.

“…Secretagogin recently cloned from a human pancreatic b-cell cDNA library by Wagner et al (2000) was also found highly expressed in human insulinoma tissue (eight copies in the cDNA library). Intracellular Ca 2þ -binding proteins such as calbindin and calretinin, which are highly homologous to secretagogin in structure, have been determined as playing central roles in the insulin release triggered by Ca 2þ flux (Redecker & Cetin 1997, Sooy et al 1999. It has been shown that insulin secretion of secretagogin-transfected RIN cells was much higher than that of controls (Wagner et al 2000).…”

Vitamin D and inflammation in the prevention of type 2 diabetes: public health relevance

“…The presence of VDRs and vitamin D binding protein (VDBP) in pancreatic β-cells has initiated studies demonstrating a relationship between single nucleotide polymorphisms (SNPs) in the genes regulating VDR, VDBP and glucose intolerance, and insulin secretion [37][38][39]. The 1α,25(OH) 2 D may be required for insulin synthesis [40] and may influence its secretion by increasing the expression of calbindin-D28K in β-cells [41]. Calbindin-D28K has an integral role in regulating intracellular calcium levels of β-cells, thus facilitating insulin exocytosis, a calcium-dependent process [41].…”

“…The 1α,25(OH) 2 D may be required for insulin synthesis [40] and may influence its secretion by increasing the expression of calbindin-D28K in β-cells [41]. Calbindin-D28K has an integral role in regulating intracellular calcium levels of β-cells, thus facilitating insulin exocytosis, a calcium-dependent process [41]. In addition to its actions on β-cell function, vitamin D may play a role in T2DM through its potent immunomodulatory functions [42][43][44].…”