RGD Reference Report - Chronic nicotine induces hypoxia inducible factor-2alpha in perinatal rat adrenal chromaffin cells: role in transcriptional upregulation of KATP channel subunit Kir6.2. - Rat Genome Database

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Chronic nicotine induces hypoxia inducible factor-2alpha in perinatal rat adrenal chromaffin cells: role in transcriptional upregulation of KATP channel subunit Kir6.2.

Authors: Salman, S  Brown, ST  Nurse, CA 
Citation: Salman S, etal., Am J Physiol Cell Physiol. 2012 May 15;302(10):C1531-8. doi: 10.1152/ajpcell.00052.2012. Epub 2012 Mar 7.
RGD ID: 7296928
Pubmed: PMID:22403787   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpcell.00052.2012   (Journal Full-text)

Fetal nicotine exposure causes impaired adrenal catecholamine secretion and increased neonatal mortality during acute hypoxic challenges. Both effects are attributable to upregulation of ATP-sensitive K(+) channels (K(ATP) channels) and can be rescued by pretreatment with the blocker, glibenclamide. Although use of in vitro models of primary and immortalized, fetal-derived rat adrenomedullary chromaffin cells (i.e., MAH cells) demonstrated the involvement of alpha7 nicotinic ACh receptor (nAChR) stimulation and the transcription factor, HIF-2alpha, the latter's role was unclear. Using Western blots, we show that chronic nicotine causes a progressive, time-dependent induction of HIF-2alpha in MAH cells that parallels the upregulation of K(ATP) channel subunit, Kir6.2. Moreover, a common HIF target, VEGF mRNA, was also upregulated after chronic nicotine. All the above effects were prevented during co-incubation with alpha-bungarotoxin (100 nM), a specific alpha7 nAChR blocker, and were absent in HIF-2alpha-deficient MAH cells. Chromatin immunoprecipitation (ChIP) assays demonstrated binding of HIF-2alpha to a putative hypoxia response element in Kir6.2 gene promoter. Specificity of this signaling pathway was validated in adrenal glands from pups born to dams exposed to nicotine throughout gestation; the upregulation of both HIF-2alpha and Kir6.2 was confined to medullary, but not cortical, tissue. This study has uncovered a signaling pathway whereby a nonhypoxic stimulus (nicotine) promotes HIF-2alpha-mediated transcriptional upregulation of a novel target, Kir6.2 subunit. The data suggest that the HIF pathway may be involved in K(ATP) channel-mediated neuroprotection during brain ischemia, and in the effects of chronic nicotine on ubiquitous brain alpha7 nAChR.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Kcnj11Ratcellular response to nicotine  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Kcnj11  (potassium inwardly-rectifying channel, subfamily J, member 11)


Additional Information