+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress



Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress



American Journal of Physiology. Heart and Circulatory Physiology 288(5): H2381-9



Cardiac norepinephrine (NE) uptake is reduced in cardiomyopathy. This change is associated with a decrease of NE transporter (NET) receptor and can be reproduced in PC12 cells by extracellular NE. 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 glycosylated 80-kDa NET and unglycosylated 46-kDa NET in the membrane and cytosolic fractions of PC12 cells. We found that NE decreased glycosylated NET in both membrane and cytosolic fractions and increased cytosolic unglycosylated NET protein. Similar results were produced by tunicamycin and thapsigargin, two agents that induce ER stress by inhibiting N-glycosylation of membrane proteins and disrupting calcium homeostasis, respectively. Also, like the ER stressors, NE not only increased 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 but also increased ER chaperone molecule glucose-regulated protein 78 and the nuclear transcription factor C/EBP homologous protein. Antioxidants superoxide dismutase and catalase prevented the downregulation of NET proteins and induction of ER stress signals produced by NE but not by tunicamycin or thapsigargin. The results indicate that the downregulation of membrane NET by NE is mediated by decreased N-glycosylation 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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 012361757

Download citation: RISBibTeXText

PMID: 15626688

DOI: 10.1152/ajpheart.00904.2004


Related references

Extracellular norepinephrine reduces neuronal uptake of norepinephrine by oxidative stress in PC12 cells. American Journal of Physiology. Heart and Circulatory Physiology 287(1): H29, 2004

Taurine protection of PC12 cells against endoplasmic reticulum stress induced by oxidative stress. Journal of Biomedical Science 17(Suppl. 1): S17, 2010

Gensenoside Rb1 protects rat PC12 cells from oxidative stress-induced endoplasmic reticulum stress: the involvement of thioredoxin-1. Molecular and Cellular Biochemistry 410(1-2): 239-246, 2015

Norepinephrine-induced oxidative stress causes PC-12 cell apoptosis by both endoplasmic reticulum stress and mitochondrial intrinsic pathway: inhibition of phosphatidylinositol 3-kinase survival pathway. American Journal of Physiology. Cell Physiology 290(5): C1373, 2006

Oxidative stress induces the endoplasmic reticulum stress and facilitates inclusion formation in cultured cells. Journal of Hepatology 47(1): 93-102, 2007

Deferoxamine induces endoplasmic reticulum stress in PC12 cells. Zeitschrift für Naturforschung. C, Journal of Biosciences 63(3-4): 308-310, 2008

Naloxone induces endoplasmic reticulum stress in PC12 cells. Molecular Medicine Reports 9(4): 1395-1399, 2014

Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells. Toxicology and Applied Pharmacology 320: 26-31, 2017

P-Nonylphenol induces endoplasmic reticulum stress-mediated apoptosis in neuronally differentiated PC12 cells. Neuroscience Letters 431(3): 256-261, 2008

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes. Laboratory Investigation 85(12): 1471-1480, 2005

Cajaninstilbene acid protects corticosterone-induced injury in PC12 cells by inhibiting oxidative and endoplasmic reticulum stress-mediated apoptosis. Neurochemistry International 78: 43-52, 2014

Imexon induces an oxidative endoplasmic reticulum stress response in pancreatic cancer cells. Molecular Cancer Research 10(3): 392-400, 2012

Exogenous norepinephrine correlates with macrophage endoplasmic reticulum stress response in association with XBP-1. Journal of Surgical Research 168(2): 262-271, 2011

Hydrogen sulfide inhibits MPP + -induced aldehyde stress and endoplasmic reticulum stress in PC12 cells: involving upregulation of BDNF. Experimental Cell Research 348(1): 106-114, 2016

Ammonia exposure induces oxidative stress, endoplasmic reticulum stress and apoptosis in hepatopancreas of pacific white shrimp (Litopenaeus vannamei). Fish and Shellfish Immunology 54: 523-528, 2016