Obstruction of ventricular Ca²⁺ -dependent arrhythmogenicity by inositol 1,4,5-trisphosphate-triggered sarcoplasmic...

Augmented inositol 1,4,5-trisphosphate (IP₃ ) receptor (IP₃ R2) expression has been linked to a variety of cardiac pathologies. Although cardiac IP₃ R2 function has been in the focus of research for some time, a detailed understanding of its potential role in ventricular myocyte excitation-contraction coupling under pathophysiological conditions remains elusive. The present study focuses on mechanisms of IP₃ R2-mediated sarcoplasmic reticulum (SR)-Ca²⁺ release in ventricular excitation-contraction coupling under IP₃ R2-overexpressing conditions by studying intracellular Ca²⁺ events. We report that, upon IP₃ R2 overexpression in ventricular myocytes, IP₃ -induced Ca²⁺ release (IP₃ ICR) modulates the SR-Ca²⁺ content via "eventless" SR-Ca²⁺ release, affecting the global SR-Ca²⁺ leak. Thus, IP₃ R2 activation could act as a SR-Ca²⁺ gateway mechanism to escape ominous SR-Ca²⁺ overload. Our approach unmasks a so far unrecognized mechanism by which "eventless" IP₃ ICR plays a protective role against ventricular Ca²⁺ -dependent arrhythmogenicity.

Augmented inositol 1,4,5-trisphosphate (IP₃ ) receptor (IP₃ R2) function has been linked to a variety of cardiac pathologies including cardiac arrhythmias. The functional role of IP₃ -induced Ca²⁺ release (IP₃ ICR) within ventricular excitation-contraction coupling (ECC) remains elusive. As part of pathophysiological cellular remodelling, IP₃ R2s are overexpressed and have been repeatedly linked to enhanced Ca²⁺ -dependent arrhythmogenicity. In this study we test the hypothesis that an opposite scenario might be plausible in which IP₃ ICR is part of an ECC protecting mechanism, resulting in a Ca²⁺ -dependent anti-arrhythmogenic response on the cellular scale. IP₃ R2 activation was triggered via endothelin-1 or IP₃ -salt application in single ventricular myocytes from a cardiac-specific IP₃ R type 2 overexpressing mouse model. Upon IP₃ R2 overexpression, IP₃ R activation reduced Ca²⁺ -wave occurrence (46 vs. 21.72%; P < 0.001) while its block increased SR-Ca²⁺ content (∼29.4% 2-aminoethoxydiphenyl borate, ∼16.4% xestospongin C; P < 0.001), suggesting an active role of IP₃ ICR in SR-Ca²⁺ content regulation and anti-arrhythmogenic function. Pharmacological separation of ryanodine receptor RyR2 and IP₃ R2 functions and two-dimensional Ca²⁺ event analysis failed to identify local IP₃ ICR events (Ca²⁺ puffs). SR-Ca²⁺ leak measurements revealed that under pathophysiological conditions, "eventless" SR-Ca²⁺ efflux via enhanced IP₃ ICR maintains the SR-Ca²⁺ content below Ca²⁺ spark threshold, preventing aberrant SR-Ca²⁺ release and resulting in a protective mechanism against SR-Ca²⁺ overload and arrhythmias. Our results support a so far unrecognized modulatory mechanism in ventricular myocytes working in an anti-arrhythmogenic fashion.