title: GRK3 regulation during CRF- and urocortin-induced CRF1 receptor desensitization.
abstract: The EC(50) values for concentration-dependent stimulation of cAMP accumulation by CRF (1.3nM) and urocortin (1.0nM) were equivalent in human retinoblastoma Y79 cells. The time course and magnitude of CRF- and urocortin-induced CRF(1) receptor desensitization were similar. A significant 3-fold increase in GRK3, but not GRK2, mRNA levels accompanied the emergence of CRF(1) receptor desensitization in Y79 cells exposed to CRF. In preliminary experiments, retinoblastoma GRK3 protein expression became upregulated during a 48-h CRF exposure. Neither GRK3 nor GRK2 expression increased in Y79 cells exposed to urocortin for 10 min to 48 h. We hypothesize that GRK3 upregulation may be a cellular negative feedback process directed at maximizing CRF(1) receptor desensitization by heightening GRK3 phosphorylating capacity during prolonged exposure to high CRF. Regulation of GRK expression associated with urocortin- and CRF-induced CRF(1) receptor desensitization appears to differ, despite a similar level of signaling via the cAMP-protein kinase A pathway.
authors.affiliation: Pharma Division, Preclinical Research, F-Hoffmann-La Roche AG, CH-4070 Basel, Switzerland. frank.dautzenberg@t-online.de
authors.forename: Frank M
authors.initials: FM
authors.lastname: Dautzenberg
authors.forename: Sandra
authors.initials: S
authors.lastname: Wille
authors.forename: Sandra
authors.initials: S
authors.lastname: Braun
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hauger
mesh_terms: D001483:Base Sequence; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers; D054770:G-Protein-Coupled Receptor Kinase 3; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology*; D012175:Retinoblastoma / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D054832:Urocortins; D000099052:CRF Receptor, Type 1
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human