Obstruction of ventricular Ca 2+ -dependent arrhythmogenicity by IP 3 - triggered SR-Ca 2+ release

Augmented inositol 1,4,5-trisphosphate (IP3) receptor (IP3R2) function has been linked to a variety of cardiac pathologies including cardiac arrhythmias. The functional role of IP3- induced Ca2+ release (IP3ICR) within ventricular excitation-contraction coupling (ECC) remains elusive. As part of pathophysiological cellular remodelling, IP3R2s 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 IP3ICR is part of an ECC protecting mechanism, resulting in a Ca2+- dependent anti-arrhythmogenic response on the cellular scale. IP3R2 activation was triggered via endothelin-1 or IP3-salt application in single ventricular myocytes from a cardiac-specific IP3R type 2 overexpressing mouse model. Upon IP3R2 overexpression, IP3R activation reduced Ca2+-wave occurrence (46% vs. 21.72%; P < 0.001) while its block increased SR-Ca2+ content (≈29.4% 2-APB, ≈16.4 % XeC; P < 0.001), suggesting an active role of IP3ICR in SR-Ca2+ content regulation and anti-arrhythmogenic function. Pharmacological separation of RyR2 and IP3R2 functions and two-dimensional Ca2+ event analysis failed to identify local IP3ICR events (Ca2+ puffs). SR-Ca2+ leak measurements revealed that under pathophysiological conditions, “eventless” SR-Ca2+ efflux via enhanced IP3ICR 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.