Cellular and Molecular Neurobiology

, Volume 30, Issue 8, pp 1451–1457 | Cite as

Stress and Adrenergic Function: HIF1α, a Potential Regulatory Switch

  • Dona Lee Wong
  • T. C. Tai
  • David C. Wong-Faull
  • Robert Claycomb
  • Brenda J. Siddall
  • Rose Ann Bell
  • Richard Kvetnansky
Review Paper
First Online:
Received:
Accepted:

Abstract

Stress elicits adrenal epinephrine and cortisol release into the bloodstream to initiate physiological and behavioral responses to counter and overcome stress, the classic “fight or flight” response (Cannon and De La Paz, Am J Physiol 28:64–70, 1911). Stress and the stress hormone epinephrine also contribute to the pathophysiology of illness, e.g., behavioral disorders, cardiovascular disease, and immune dysfunction. Epinephrine itself is regulated by stress through its biosynthesis by phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28). Single and repeated immobilization (IMMO) stress in rats stimulates adrenal PNMT mRNA and protein expression via the transcription factors, Egr-1 and Sp1. Moderate hypoxic stress increases PNMT promoter-driven gene expression and endogenous PNMT mRNA and protein in PC12 cells. Induction is initiated through cAMP and PLC signaling, with PKA, PKC, PI3K, ERK1/2 MAPK, and p38 MAPK continuing downstream signal transduction, followed by activation of HIF1α, Egr-1, and Sp1. While functional Egr-1 and Sp1 binding sites exist within the proximal PNMT promoter, a putative hypoxia response element is a weak HIF binding site. Yet, HIF1α overexpression increases PNMT promoter-driven luciferase activity and endogenous PNMT. When the Egr-1 or Sp1 sites are mutated, HIF1α does not stimulate the PNMT promoter. siRNA knock down of Egr-1 or Sp1 prevents promoter activation while siRNA knock down of HIF1α inhibits Egr-1 and Sp1 induction. Findings suggest that hypoxia activates the PNMT gene indirectly via HIF1α stimulation of Egr-1 and Sp1. Thus, for stress-induced illnesses where adrenergic dysfunction is implicated, HIF1α may be an “on–off” switch regulating adrenergic responses to stress and a potential target for therapeutic intervention.

Keywords

Stress Phenylethanolamine N-methyltransferase Transcriptional control Egr-1 Sp1 HIF1α 
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Notes

Acknowledgments

This study was supported by The Spunk Fund, Inc., the Sobel-Keller Research Fund, McLean Hospital, and the Emerald Foundation, Inc. (DLW), and Slovak Grants, APVV-0148-06 and VEGA 2/0133/08 (RK).

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Dona Lee Wong
    • 1
    • 2
  • T. C. Tai
    • 1
    • 2
    • 3
  • David C. Wong-Faull
    • 1
  • Robert Claycomb
    • 1
  • Brenda J. Siddall
    • 2
  • Rose Ann Bell
    • 2
  • Richard Kvetnansky
    • 4
  1. 1.Department of Psychiatry, Harvard Medical School, Laboratory of Molecular and Developmental NeurobiologyMcLean HospitalBelmontUSA
  2. 2.Department of Psychiatry and Behavioral Sciences, The Nancy Pritzker Laboratory of Developmental and Molecular NeurobiologyStanford University School of MedicineStanfordUSA
  3. 3.Division of Medicine, Northern Ontario School of MedicineLaurentian UniversitySudburyCanada
  4. 4.Institute of Experimental EndocrinologySlovak Academy of SciencesBratislavaSlovakia

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