LAUSR

AIMS β-Adrenergic receptors (βARs) play pivotal roles in regulating cardiac excitation-contraction (E-C) coupling. Global signaling of β1ARs upregulates both the influx of Ca2+ through sarcolemmal L-type Ca2+ channels (LCCs) and the release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptors (RyRs). However, we recently found that β2AR stimulation meditates "offside compartmentalization", confining β1AR signaling into subsarcolemmal nanodomains without reaching SR proteins. In the present study, we aim to investigate the new question whether and how compartmentalized β1AR signaling regulates cardiac E-C coupling. METHODS AND RESULTS By combining confocal Ca2+ imaging and patch clamp techniques, we investigated the effects of compartmentalized βAR signaling on E-C coupling at both cellular and molecular levels. We found that simultaneous activation of β2 and β1ARs, in contrast to global signaling of β1ARs, modulated neither the amplitude and spatiotemporal properties of Ca2+ sparks nor the kinetics of the RyR response to LCC Ca2+ sparklets. Nevertheless, by upregulating LCC current, compartmentalized β1AR signaling synchronized RyR Ca2+ release and increased the functional reserve (stability margin) of E-C coupling. In circumstances of briefer excitation durations or lower RyR responsivity, compartmentalized βAR signaling, by increasing the intensity of Ca2+ triggers, helped stabilize the performance of E-C coupling and enhanced the Ca2+ transient amplitude in failing heart cells. CONCLUSION Given that compartmentalized βAR signaling can be induced by stress-associated levels of catecholamines, our results revealed an important, yet unappreciated, heart regulation mechanism that is autoadaptive to varied stress conditions.