PMID- 21193559
OWN - NLM
STAT- MEDLINE
DCOM- 20110804
LR  - 20211020
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 25
IP  - 2
DP  - 2011 Feb
TI  - PERK activation at low glucose concentration is mediated by SERCA pump inhibition 
      and confers preemptive cytoprotection to pancreatic beta-cells.
PG  - 315-26
LID - 10.1210/me.2010-0309 [doi]
AB  - Protein kinase R-like ER kinase (PERK) is activated at physiologically low 
      glucose concentrations in pancreatic beta-cells. However, the molecular mechanisms 
      by which PERK is activated under these conditions and its role in beta-cell function 
      are poorly understood. In this report, we investigated, in dispersed rat islets 
      of Langerhans and mouse insulinoma-6 (MIN6) cells, the relationship between 
      extracellular glucose concentration, the free endoplasmic reticulum (ER) calcium 
      concentration ([Ca(2+)](ER)) measured directly using an ER targeted fluorescence 
      resonance energy transfer-based calcium sensor, and the activation of PERK. We 
      found that a decrease in glucose concentration leads to a concentration-dependent 
      reduction in [Ca(2+)](ER) that parallels the activation of PERK and the 
      phosphorylation of its substrate eukaryotic initiation factor-2alpha. We provide 
      evidence that this decrease in [Ca(2+)](ER) is caused by a decrease in 
      sarcoplasmic/ER Ca(2+)-ATPase pump activity mediated by a reduction in the energy 
      status of the cell. Importantly, we also report that PERK-dependent eukaryotic 
      initiation factor-2alpha phosphorylation at low glucose concentration plays a 
      significant role in 1) the regulation of both proinsulin and global protein 
      synthesis, 2) cell viability, and 3) conferring preemptive cytoprotection against 
      ER stress. Taken together, these results provide evidence that a decrease in the 
      ATP/energy status of the cell in response to a decrease in glucose concentration 
      results in sarcoplasmic/ER Ca(2+)-ATPase pump inhibition, the efflux of Ca(2+) 
      from the ER, and the activation of PERK, which plays an important role in both 
      pancreatic beta-cell function and survival.
FAU - Moore, Claire E
AU  - Moore CE
AD  - Department of Cell Physiology and Pharmacology, The Henry Wellcome Building, 
      University of Leicester, University Road, Leicester LE1 9HN, United Kingdom.
FAU - Omikorede, Omotola
AU  - Omikorede O
FAU - Gomez, Edith
AU  - Gomez E
FAU - Willars, Gary B
AU  - Willars GB
FAU - Herbert, Terence P
AU  - Herbert TP
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - BB_/Biotechnology and Biological Sciences Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101230
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 9035-68-1 (Proinsulin)
RN  - EC 2.7.11.1 (PERK kinase)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - IY9XDZ35W2 (Glucose)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum/*metabolism
MH  - Enzyme Activation
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - Flow Cytometry
MH  - Fluorescence Resonance Energy Transfer
MH  - Glucose/*metabolism
MH  - Insulin-Secreting Cells/cytology/*metabolism
MH  - Islets of Langerhans/metabolism
MH  - Male
MH  - Mice
MH  - Phosphorylation
MH  - Proinsulin/biosynthesis
MH  - Protein Biosynthesis
MH  - Rats
MH  - Rats, Wistar
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/*antagonists & 
      inhibitors/metabolism
MH  - eIF-2 Kinase/*metabolism
PMC - PMC3070211
EDAT- 2011/01/05 06:00
MHDA- 2011/08/05 06:00
PMCR- 2010/12/30
CRDT- 2011/01/04 06:00
PHST- 2011/01/04 06:00 [entrez]
PHST- 2011/01/05 06:00 [pubmed]
PHST- 2011/08/05 06:00 [medline]
PHST- 2010/12/30 00:00 [pmc-release]
AID - me.2010-0309 [pii]
AID - me-10-0309 [pii]
AID - 10.1210/me.2010-0309 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2011 Feb;25(2):315-26. doi: 10.1210/me.2010-0309. Epub 2010 Dec 
      30.