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Rationale: βARs (β-adrenergic receptors) are prototypical GPCRs (G protein–coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, β1 AR signaling mediates a global response, including bothl -type Ca2+ channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sarcoplasmic reticulum). In contrast, β2 AR mediates local signaling with little effect on the function of SR proteins.Objective: To investigate the signaling relationship between β1 ARs and β2 ARs.Method and Results: Using whole-cell patch-clamp analyses combined with confocal Ca2+ imaging, we found that the activation of compartmentalized β2 AR signaling was able to convert the β1 AR signaling from global to local mode, preventing β1 ARs from phosphorylating RyRs that were only nanometers away from sarcolemma/T tubules. This offside compartmentalization was eliminated by selective inhibition of β2 AR, GRK2 (GPCR kinase-2), βarr1 (β-arrestin-1), and phosphodiesterase-4. A knockin rat model harboring mutations of the last 3 serine residues of the β1 AR C terminus, a component of the putative βarr1 binding site and GRK2 phosphorylation site, eliminated the offside compartmentalization conferred by β2 AR activation.Conclusions: β2 AR stimulation compartmentalizes β1 AR signaling into nanoscale local domains in a phosphodiesterase-4–dependent manner by targeting the C terminus of β1 ARs. This finding reveals a fundamental negative feed-forward mechanism that serves to avoid the cytotoxicity of circulating catecholamine and to sharpen the transient β1 AR response of sympathetic excitation.

circulation research

β 2 -Adrenergic Stimulation Compartmentalizes β 1 Signaling Into Nanoscale Local Domains by Targeting the C-Terminus of β 1 -Adrenoceptors