Compartmentalized β1-Adrenergic Signaling Synchronizes Excitation-contraction Coupling Without Modulating Individual Ca2+ Sparks in Healthy and Hypertrophied Cardiomyocytes.

Aims beta-adrenergic receptors (beta ARs) play pivotal roles in regulating cardiac excitation-contraction (E-C) coupling. Global signalling of beta(1)ARs up-regulates 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 beta(2)AR stimulation meditates 'offside compartmentalization', confining beta(1)AR signalling into subsarcolemmal nanodomains without reaching SR proteins. In the present study, we aim to investigate the new question, whether and how compartmentalized beta(1)AR signalling regulates cardiac E-C coupling. Methods and results By combining confocal Ca2+ imaging and patch-clamp techniques, we investigated the effects of compartmentalized beta AR signalling on E-C coupling at both cellular and molecular levels. We found that simultaneous activation of beta(2) and beta(1)ARs, in contrast to global signalling of beta(1)ARs, modulated neither the amplitude and spatiotemporal properties of Ca2+ sparks nor the kinetics of the RyR response to LCC Ca2+ sparklets. Nevertheless, by up-regulating LCC current, compartmentalized beta(1)AR signalling 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 beta AR signalling, 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 beta AR signalling 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.