|dc.description.abstract||The functions of the phosphodiesterase 8 family of cyclic nucleotide phosphodiesterases (PDEs) have been largely unexplored, primarily due to the lack of selective pharmacological inhibitors. The main function of PDEs is to degrade cAMP, a ubiquitous second messenger, and therefore regulate intracellular levels of cAMP. Here we report that PDE8B is highly enriched in mouse adrenal fasiculata cells and in the hippocampal and striatal regions of the mouse brain. Furthermore, we show that PDE8B regulates known cAMP-dependent physiological processes in those tissues, specifically in adrenal steroidogenesis, anxiety-like behaviors, and potentially learning and memory.
Corticosterone, the major murine glucocorticoid, is synthesized by adrenal fasciculata cells in response to adrenocorticotropin (ACTH) in a cAMP/PKA (protein kinase A) dependent manner. Activation of PKA promotes corticosterone production by increasing substrate availability, phosphorylation of key enzymes, and transcription of steroidogenic enzymes. We show that inhibition of PDE8B increases the basal level adrenal steroids and the responsiveness of the fasciculate cells towards ACTH. We also find that PDE8B knockout mice have elevated urinary corticosterone even though the circulating ACTH is repressed, presumably due to adrenal hypersensitivity in vivo. Furthermore, the adrenal glands from PDE8B KO mice have higher levels of several key steroidogenic enzymes, and acute inhibition of PDE8B with a newly characterized PDE8-selective inhibitor (PF-04957325) also increases PKA phosphorylation of several substrates. We conclude that PDE8B is a negative modulator of one or more pools of cAMP that promotes steroidogenesis via both chronic and acute mechanisms.
cAMP has also been implicated in a number of animal behaviors, such as anxiety and memory formation. We investigated if PDE8B also regulates the pools of cAMP which are important for those behaviors. First, we showed that PDE8B KO mice exhibited anxiety-like behaviors when tested with the elevated plus maze and open field test. PDE8B KO mice did not show a robust enhancement in learning, however these mice appeared to be more efficient in acquiring a task in the Morris water maze. We conclude that PDE8B KO mice exhibit anxiety-like behaviors and potentially have a subtle learning and memory phenotype.||en_US