Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells.
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.
Dror
Vardit
V
Laboratory of Molecular Signaling in Diabetes, Diabetes Research Group, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
Kalynyak
Tatyana B
TB
Bychkivska
Yaryna
Y
Frey
Matthew H Z
MH
Tee
May
M
Jeffrey
Kristin D
KD
Nguyen
Vy
V
Luciani
Dan S
DS
Johnson
James D
JD
D000244:Adenosine Diphosphate / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*
C497396:ARNT protein, human; D053764:Presenilin-1; D020033:Protein Isoforms; D019837:Ryanodine Receptor Calcium Release Channel; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002154:Calpain; C415197:calpain 10; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium