PDE4B mediates local feedback regulation of β₁-adrenergic cAMP signaling in a sarcolemmal compartment of cardiac myocytes.

Multiple cAMP phosphodiesterase (PDE) isoforms play divergent roles in cardiac homeostasis but the molecular basis for their non-redundant function remains poorly understood. Here, we report a novel role for the PDE4B isoform in β-adrenergic (βAR) signaling in the heart. Genetic ablation of PDE4B disrupted βAR-induced cAMP transients, as measured by FRET sensors, at the sarcolemma but not in the bulk cytosol of cardiomyocytes. This effect was further restricted to a subsarcolemmal compartment because PDE4B regulates β1AR-, but not β2AR- or PGE2-induced responses. The spatially restricted function of PDE4B was confirmed by its selective effects on phosphorylation patterns. PDE4B limited the duanyu1529-mediated phosphorylation of key players in excitation-contraction coupling that reside in the sarcolemmal compartment, including L-type Ca(2+) channels and ryanodine receptors, but not phosphorylation of distal cytosolic proteins. β1AR- but not β2AR-ligation induced activation of PDE4B and interruption of this negative feedback with inhibitors increased sarcolemmal cAMP. Thus, PDE4B mediates a crucial duanyu1529-dependent feedback that controls β1AR-dependent cAMP signals in a restricted subsarcolemmal domain. Disruption of this feedback augments local signals, leading to an increased intracellular Ca(2+) level and contraction rate.

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