title: The high-affinity cAMP-specific phosphodiesterase 8B controls steroidogenesis in the mouse adrenal gland.
abstract: The functions of the phosphodiesterase 8B (PDE8) family of phosphodiesterases have been largely unexplored because of the unavailability of selective pharmacological inhibitors. Here, we report a novel function of PDE8B as a major regulator of adrenal steroidogenesis using a genetically ablated PDE8B mouse model as well as cell lines treated with either a new PDE8-selective inhibitor or a short hairpin RNA (shRNA) construct against PDE8B. We demonstrate that PDE8B is highly enriched in mouse adrenal fasciculata cells, and show that PDE8B knockout mice have elevated urinary corticosterone as a result of adrenal hypersensitivity toward adrenocorticotropin. Likewise, ablation of PDE8B mRNA transcripts by an shRNA construct potentiates steroidogenesis in the commonly used Y-1 adrenal cell line. We also observed that the PDE8-selective inhibitor (PF-04957325) potentiates adrenocorticotropin stimulation of steroidogenesis by increasing cAMP-dependent protein kinase activity in both primary isolated adrenocortical cells and Y-1 cells. It is noteworthy that PDE8s have their greatest control under low adrenocorticotropin-stimulated conditions, whereas other higher K(m) PDE(s) modulate steroidogenesis more effectively when cells are fully stimulated. Finally, both genetic ablation of PDE8B and long-term pharmacological inhibition of PDE8s cause increased expression of steroidogenic enzymes. We conclude that PDE8B is a major regulator of one or more pools of cAMP that promote steroidogenesis via both short- and long-term mechanisms. These findings further suggest PDE8B as a potential therapeutic target for the treatment of several different adrenal diseases.
authors.affiliation: University of Washington, Department of Pharmacology, Seattle, WA 98195-7280, USA.
authors.forename: Li-Chun Lisa
authors.initials: LC
authors.lastname: Tsai
authors.forename: Masami
authors.initials: M
authors.lastname: Shimizu-Albergine
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Beavo
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D000302:Adrenal Cortex / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D013256:Steroids; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C520790:Pde8a protein, mouse