Abstract
Pancreatic beta-cell death is a critical event in type 1 diabetes, type 2 diabetes, and clinical islet transplantation. We have previously shown that prolonged block of ryanodine receptor (RyR)-gated release from intracellular Ca(2+) stores activates calpain-10-dependent apoptosis in beta-cells. In the present study, we further characterized intracellular Ca(2+) channel expression and function in human islets and the MIN6 beta-cell line. All three RyR isoforms were identified in human islets and MIN6 cells, and these endoplasmic reticulum channels were observed in close proximity to mitochondria. Blocking RyR channels, but not sarco/endoplasmic reticulum ATPase (SERCA) pumps, reduced the ATP/ADP ratio. Blocking Ca(2+) flux through RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of hypoxia-inducible factor (HIF-1beta). Moreover, inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1beta and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1beta, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signaling network in beta-cells. We demonstrate that this pathway is controlled by Ca(2+) flux through intracellular channels, likely via changes in mitochondrial metabolism and ATP. These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca(2+) homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.
Highlights
Inappropriate activation of pancreatic -cell death pathways is involved in the pathogenesis of type 1 diabetes, type 2 diabetes, and several other forms of the disease [1,2,3,4]
These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca2؉ homeostasis and metabolic activity are suppressed in diabetes and islet transplantation
We have recently shown that intracellular Ca2ϩ stores gated by the ryanodine receptor Ca2ϩ release channel (RyR)4 are essential for -cell survival in vitro [6], but not for glucose-stimulated insulin release [7]
Summary
RyR, ryanodine receptor; ER, endoplasmic reticulum; HIF, hypoxia-inducible factor; IP3R, inositol trisphosphate receptor; SERCA, sarcoplasmic reticulum ATPase. The signals that regulate hypoxia-inducible factors in -cells are poorly characterized. Another family of proteins that has been implicated in the response to reduced cellular metabolic activity is the presenilins. HIF-1␣ mRNA was identified as one of the most upregulated targets of presenilin-1 by both microarray [27] and differential display [28] It is not known whether ryanodineinduced -cell death or hypoglycemia [6] triggers this pathway. We sought to identify novel components of a -cell survival gene network linked to RyR. We determined that overexpression of presenilin-1 increased the levels of HIF-1 protein Together these results provide the first evidence of a RyR-presenilin-HIF genetic network controlling -cell survival
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