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J. Biol. Chem., Vol. 283, Issue 15, 9909-9916, April 11, 2008

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Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells^*

From the Laboratory of Molecular Signaling in Diabetes, Diabetes Research Group, Department of Cellular and Physiological Sciences, and the Department of Surgery, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

Pancreatic β-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 Ca²⁺ stores activates calpain-10-dependent apoptosis in β-cells. In the present study, we further characterized intracellular Ca²⁺ channel expression and function in human islets and the MIN6 β-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 Ca²⁺ flux through RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of hypoxia-inducible factor (HIF-1β). Moreover, inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1β and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1β, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signaling network in β-cells. We demonstrate that this pathway is controlled by Ca²⁺ 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 Ca²⁺ homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.

Received for publication, December 31, 2007

^* This work was supported in part by operating grants from the Canadian Institutes for Health Research (CIHR MOP-69012) and the Natural Sciences and Engineering Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a postdoctoral fellowship from the Stem Cell Network and the Juvenile Diabetes Research Foundation (JDRF).

² Supported by a JDRF fellowship.

³ To whom correspondence should be addressed: Diabetes Research Group, Dept. of Cellular and Physiological Sciences and Dept. of Surgery, University of British Columbia, 5358 Life Sciences Bldg., 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Fax: 604-822-2316; E-mail: jimjohn{at}interchange.ubc.ca.