Glucocorticoids differentially regulate the expression of CRFR1 and CRFR2α in MIN6 insulinoma cells and rodent islets

M. O. Huising, A. P. Pilbrow, M. Matsumoto, T. Van Der Meulen, H. Park, J. M. Vaughan, S. Lee, W. W. Vale

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Urocortin 3 (Ucn 3), member of the corticotropin-releasing factor (CRF) family of peptide hormones, is released from β-cells to potentiate insulin secretion. Ucn 3 activates the CRF type-2 receptor (CRFR2) but does not activate the type-1 receptor (CRFR1), which was recently demonstrated on β-cells. While the direct actions of Ucn 3 on insulin secretion suggest the presence of cognate receptors within the islet microenvironment, this has not been established. Here we demonstrate that CRFR2β is expressed by MIN6 insulinoma cells and by primary mouse and human islets, with no detectable expression of CRFR2β. Furthermore, stimulation of MIN6 cells or primary mouse islets in vitro or in vivo with glucocorticoids (GCs) robustly and dose-dependently increases the expression of CRFR2β, while simultaneously inhibiting the expression of CRFR1 and incretin receptors. Luciferase reporters driven by the mouse CRFR1 or CRFR2β promoter in MIN6 cells confirm these differential effects of GCs. In contrast, GCs inhibit CRFR2β promoter activity in HEK293 cells and inhibit the expression of CRFR2β in A7r5 rat aortic smooth muscle cells and differentiated C2C12 myotubes. These findings suggest that the GC-mediated increase of CRFR2β depends on the cellular context of the islet and deviates from the GC-mediated suppression of CRFR1 and incretin receptors. Furthermore, GC-induced increases in CRFR2β expression coincide with increased Ucn 3-dependent activation of cAMP and MAPK pathways. We postulate that differential effect of GCs on the expression of CRFR1 and CRFR2β in the endocrine pancreas represent a mechanism to shift sensitivity from CRFR1 to CRFR2 ligands.

Original languageEnglish (US)
Pages (from-to)138-150
Number of pages13
JournalEndocrinology
Volume152
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

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