The high affinity cAMP - specific phosphodiesterase 8 B ( PDE 8 B ) controls steroidogenesis in the mouse adrenal gland

The functions of the PDE8 family of phosphodiesterases have been largely unexplored due to 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 an 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 due to adrenal hypersensitivity toward ACTH. Similarly, acute ablation of PDE8B mRNA transcripts by an shRNA construct potentiates steroiodogenesis in the commonly used Y-1 adrenal cell line. We also observed that the PDE8-selective inhibitor (PF-04957325) acutely potentiates ACTH stimulation of steroidogenesis by increasing PKA activity in both primary isolated adrenocortical cells and Y-1 cells. Interestingly, PDE8s have their greatest control under low ACTH-stimulated conditions while other higher K m PDE(s) modulate steroidogenesis more effectively when cells are fully stimulated. Finally, both genetic ablation of PDE8B and chronic 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 acute and chronic mechanisms. These findings further suggest PDE8B as a potential therapeutic target for the treatment of several different adrenal diseases.