The High-Affinity cAMP-Specific Phosphodiesterase 8B Controls Steroidogenesis in the Mouse Adrenal Gland
- 27 December 2010
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 79 (4), 639-648
- https://doi.org/10.1124/mol.110.069104
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 Km 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.Keywords
This publication has 33 references indexed in Scilit:
- PDE8 Regulates Rapid Teff Cell Adhesion and Proliferation Independent of ICERPLOS ONE, 2010
- Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectivesMolecular Human Reproduction, 2009
- The adrenal cortex and lifeMolecular and Cellular Endocrinology, 2009
- A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortexEuropean Journal of Human Genetics, 2008
- Molecular aspects of adrenal regulation for circadian glucocorticoid synthesis by chronic voluntary exerciseLife Sciences, 2007
- Modulation of Leydig cell function by cyclic nucleotide phosphodiesterase 8AProceedings of the National Academy of Sciences of the United States of America, 2006
- Phytoestrogen Resveratrol Suppresses Steroidogenesis by Rat Adrenocortical Cells by Inhibiting Cytochrome P450 c21-HydroxylaseHormone Research in Paediatrics, 2005
- Rat glomerulosa cells in primary culture and E. coli lipopolysaccharide actionThe Journal of Steroid Biochemistry and Molecular Biology, 2003
- Hormone-sensitive lipaseJournal of Lipid Research, 2002
- ACTH induces up-regulation of ACTH receptor mRNA in mouse and human adrenocortical cell linesMolecular and Cellular Endocrinology, 1994