AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol (December 30, 2004). doi:10.1152/ajpheart.00904.2004
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Submitted on August 31, 2004
Accepted on December 29, 2004

Norepinephrine induces endoplasmic reticulum stress and down-regulation of norepinephrine transporter density in PC12 cells via oxidative stress

Weike Mao1, Chikao Iwai1, Fuzhong Qin1, and Chang-seng Liang1*

1 Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA

* To whom correspondence should be addressed. E-mail: chang-seng_liang{at}urmc.rochester.edu.

Reduced cardiac norepinephrine (NE) uptake function is a salient feature of congestive heart failure. We have shown that this decrease in NE uptake, associated with NE transporter (NET) receptor down-regulation, is mediated via increased cardiac NE release in animals, and can be reproduced in PC12 cells by extracellular NE. Furthermore, since NET mRNA does not change, we speculate that the decrease of NET protein by NE is a post-transcriptional event, mediated via an action of NE-derived oxidative metabolites on the sympathetic neurons. To study whether this effect of NE is mediated via impaired glycosylation and trafficking of NET in the endoplasmic reticulum (ER), we measured the distribution of mature glycosylated 80 kDa NET and unglycosylated 46 kDa NET in the membrane and cytosolic fractions of PC12 cells. We found that the reduction of PC12 cell membrane NET density by NE was associated with a decrease of glycosylated NET in both membrane and cytosolic fractions, and an increase of unglycosylated NET protein inside the cell. Qualitatively similar changes of NET proteins were produced by tunicamycin and thapsigargin, two agents which induce ER stress by inhibiting Nglycosylation of membrane proteins and disrupting calcium homeostasis, respectively. Also like the ER stressors, NE caused a gradual increase in phosphorylation of both the {alpha}-subunit of eukaryotic initiation factor-2 and its upstream RNA-dependent protein kinase like ER kinase over 12 h of treatment. ER stress was also evidenced by increased ER chaperone molecule glucose regulated protein 78 and the nuclear transcription factor C/EBP homologous protein. Pretreatment of PC12 cells with antioxidants superoxide dismutase and catalase prevented the downregulation of NET proteins, and induction of ER stress signals. In contrast, antioxidants had no effects on the reduction of NET and increased ER stress signals induced by tunicamycin and thapsigargin. Results of our study indicate that the downregulation of membrane NET byNE is mediated by decreased N-glyocosylation of NET proteins secondary to induction of ER stress pathways by NE derived oxidative metabolites. Interventions involving the ER stress pathways may provide novel therapeutic strategies for the treatment of sympathetic dysfunction in heart failure.




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