The pumping action of the heart is tightly regulated by many factors. For example, the ion channel proteins RyR2 and SERCA2a regulate cardiac contraction via the β adrenergic receptor (βAR) pathway and under stress conditions, βAR stimulation promotes the enzyme activity of PKA to ultimately enhance cardiac contraction and relaxation. However, it’s unclear exactly how βAR-stimulated PKA dynamically affects RyR2 and SERCA2a within their nano-scale subcellular domains. To learn more, researchers recently used biosensors to detect PKA activity at these nanodomains in heart cells from mice, rats, and rabbits. They found that the βAR subtype β₁AR signaled to both RyR2 and SERCA2a nanodomains via PKA, while β₂AR did not. Specifically, β₂AR signaling at these nanodomains was prevented by the enzymes PDE3 and PDE4, which controlled baseline PKA activity, but blocking an inhibitory G protein permitted β₂AR signaling at the RyR2 nanodomains. Although the biosensor results should be confirmed through other approaches, this study reveals new details of βAR-mediated cardiac signaling that may help clarify the precise regulation of cardiac output under normal and pathological conditions.