Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

H.H. Stolte, B.M.L. Verburg-van Kemenade, H.F.J. Savelkoul, G. Flik

Research output: Contribution to journalArticleAcademicpeer-review

126 Citations (Scopus)


Glucocorticoids (GCs) are commonly used to treat a variety of immune diseases. However, the efficacy of treatment is greatly influenced by an individual variation in sensitivity to GCs, which is caused by differences in the glucocorticoid receptor (GR). The variable receptor profile results from variations in the GR gene, or alternative splicing of the gene coded. We investigated the evolution of the GR gene by comparing genomic GR sequences of vertebrates. Exon length and amino acid sequence are conserved among all classes of vertebrates studied, which indicates strong evolutionary pressure on conservation of this gene. Interestingly, teleostean fishes have two different GR proteins. One of the duplicate fish GR, genes has a nine-amino-acid insert in the DNA binding region that results from alternative splicing. The duplicate GR genes and products of alternative splicing in teleostean fishes are differentially expressed in vivo and show different transactivation capacity in vitro. The presence of two GR genes appears to be a result of divergence of receptors rather than of ligands. Teleostean fishes express different, evolutionarily related, functional GR proteins within a single organism. Hereby, teleostean fishes present a model that facilitates investigation of the molecular basis of cortisol resistance and different regulatory functions of cortisol
Original languageEnglish
Pages (from-to)17-28
Number of pages12
JournalJournal of Endocrinology
Issue number1
Publication statusPublished - 2006


  • dna-binding domain
  • cyprinus-carpio l
  • teleost fish
  • guinea-pig
  • steroid sensitivity
  • hormone-receptors
  • plasma-cortisol
  • stress-response
  • common carp
  • mechanisms


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