Open AccessHyperactive Human Glucocorticoid Receptor Isoforms and their Implications for the Stress Response
Author(s) -
Michael V. Lasker,
Stacey M. Leventhal,
Debora Lim,
Tajia L. Green,
Kelly Tung,
Ki-Ho Cho,
David G. Greenhalgh
Publication year - 2015
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/shk.0000000000000289
Subject(s) - glucocorticoid receptor , transactivation , snp , single nucleotide polymorphism , gene isoform , glucocorticoid , endocrinology , medicine , biology , receptor , septic shock , genetics , gene , sepsis , gene expression , genotype
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 among individuals in response to stress or shock.