title: Modulation of signaling through GPCR-cAMP-PKA pathways by PDE4 depends on stimulus intensity: Possible implications for the pathogenesis of acrodysostosis without hormone resistance.
abstract: In acrodysostosis without hormone resistance, a disease caused by phosphodiesterase (PDE)-4D mutations, increased PDE activity leads to bone developmental defects but with normal renal responses to PTH. To identify potential mechanisms for these disparate responses, we compared the effect of PDE activity on hormone signaling through the GPCR-Gsα-cAMP-PKA pathway in cells from two lineages, HEK-293 cells stably overexpressing PTH1R (HEKpthr) and human dermal fibroblasts, including studies evaluating cAMP levels using an Epac-based BRET-sensor for cAMP (CAMYEL). For ligand-induced responses inducing strong cAMP accumulation, the inhibition of PDE4 activity resulted in relatively small further increases. In contrast, when ligand-induced cAMP accumulation was of lesser intensity, the inhibition of PDE4 had a more pronounced effect. Similar results were obtained evaluating downstream events (cellular CREB phosphorylation and CRE-luciferase activity). Thus, the ability of PDE4 to modulate signaling through GPCR-cAMP-PKA pathways can depend on the cell type and stimulus intensity.
authors.affiliation: INSERM U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Motte
authors.affiliation: INSERM U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Le Stunff
authors.affiliation: INSERM U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Briet
authors.affiliation: INSERM U976, Institut de Recherche sur la Peau, Hôpital Saint Louis, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
authors.affiliation: INSERM U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France; Centre de Référence des Maladies Rares du Métabolisme du Phosphore et du Calcium, Assistance Publique Hôpitaux de Paris, Paris, France; Service de Biochimie et Génétique Moléculaires, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France. Electronic address: caroline.silve@inserm.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Silve
mesh_terms: D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004413:Dysostoses / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D006728:Hormones; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Acrodysostosis; BRET; Hormonal response; Inhibition; PDE4D; cAMP