Hyperactive Human Glucocorticoid Receptor Isoforms and Their Implications for the Stress Response

Michael V. Lasker, Stacey M. Leventhal, Debora Lim, Tajia L. Green, Kelly Tung, Kiho Cho, David G Greenhalgh

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

ABSTRACT: Glucocorticoids are indispensable therapeutic agents in diseases of inflammation, but their effectiveness in treating advanced septic shock has been inconsistent. Our understanding of the mechanisms causing this variability to steroid therapy remains limited. Previous studies in our laboratory have implicated human glucocorticoid receptor (hGR) polymorphisms as one of the likely reasons for this variability. We examined the effect of two single nucleotide polymorphisms (SNPs) on the transactivation potential of the hGR in the absence and presence of exogenous steroids. An isoform containing a novel naturally-occurring human SNP, T1463C, was found to have a hyperactive response with treatment of all three steroids examined, while maintaining low activity in the absence of steroids, relative to reference hGR. In comparison, another hGR isoform with the A2297G SNP, previously identified in our laboratory, demonstrated hyperactive transactivational response in the absence of steroids, however, it had a significant increase in activity after treatment with only one of the glucocorticoids (hydrocortisone) tested. These results offer a possible explanation for the clinical variability seen amongst individuals in response to stress or shock.

Original languageEnglish (US)
JournalShock
DOIs
StateAccepted/In press - Nov 12 2014

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

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