Phosphodiesterase 4D is required for beta2 adrenoceptor subtype-specific signaling in cardiac myocytes.

beta adrenoceptor (betaAR) signaling is finely regulated to mediate the sympathetic nervous system control of cardiovascular function. In neonatal cardiac myocytes, beta1AR activates the conventional Gs/cAMP pathway, whereas beta2AR sequentially activates both the Gs and Gi pathways to regulate the myocyte contraction rate. Here, we show that phosphodiesterase 4D (PDE4D) selectively impacts signaling by beta2AR in neonatal cardiac myocytes, while having little or no effect on beta1AR signaling. Although beta2AR activation leads to an increase in cAMP production, the cAMP generated does not have access to the protein kinase A-dependent signaling pathways by which the beta1AR regulates the contraction rate. However, this restricted access is lost in the presence of PDE4 inhibitors or after ablation of PDE4D. These results not only suggest that PDE4D is an integral component of the beta2AR signaling complex, but also underscore the critical role of subcellular cAMP regulation in the complex control of receptor signaling. They also illustrate a mechanism for fine-tuned betaAR subtype signaling specificity and intensity in the cardiac system.