title: Glucocorticoids differentially regulate the expression of CRFR1 and CRFR2α in MIN6 insulinoma cells and rodent islets.
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 CRFR2α 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 CRFR2α, while simultaneously inhibiting the expression of CRFR1 and incretin receptors. Luciferase reporters driven by the mouse CRFR1 or CRFR2α promoter in MIN6 cells confirm these differential effects of GCs. In contrast, GCs inhibit CRFR2α 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 CRFR2α 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 CRFR2α 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 CRFR2α in the endocrine pancreas represent a mechanism to shift sensitivity from CRFR1 to CRFR2 ligands.
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: M O
authors.initials: MO
authors.lastname: Huising
authors.forename: A P
authors.initials: AP
authors.lastname: Pilbrow
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: van der Meulen
authors.forename: H
authors.initials: H
authors.lastname: Park
authors.forename: J M
authors.initials: JM
authors.lastname: Vaughan
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: W W
authors.initials: WW
authors.lastname: Vale
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003345:Corticosterone / Q000494:pharmacology*; D004343:Drug Implants; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007340:Insulinoma / Q000188:drug therapy / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D015735:Mifepristone; D020033:Protein Isoforms; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D004343:Drug Implants; D005938:Glucocorticoids; D020033:Protein Isoforms; D018019:Receptors, Corticotropin-Releasing Hormone; D015735:Mifepristone; D000099052:CRF Receptor, Type 1; D003345:Corticosterone