Insights into the Physiological Functions of PDE4 from Knockout Mice

phosphodiesterases 4 (PDE4s) are involved in a plethora of physiological processes as documented by the wide array of phenotypes detected in the PDE4 KO mice. The role of PDE4 in subtype-specific β-adrenoceptor signaling has been further dissected using knockout mice for the β₁-adrenergic receptor (AR) and β₂-AR. That a PDE serves indispensable functions in the body is underscored by the loss of viability of PDE4 knockout mice. Neonatal lethality and growth retardation are the prominent phenotypes in mice with targeted disruption of the PDE4D gene. Gonadal function depends on the pituitary gonadotropins FSH and luteinizing hormone, which exert their effects through activation of cyclic nucleotide signaling. Biochemical studies using purified peritoneal naive macrophages have further defined the role of PDE4 in Toll-like receptors signaling. PDE4 is the predominant 3',5'-cyclic adenosine monophosphate-degrading isozyme in neutrophils recovered from the bronchoalveolar lavage of wild-type mice.