Ca2+ triggered arrhythmias, a seesaw game between SR Ca2+ release and uptake?

VALVERDE, CARLOS A; CELY-ORTIZ, ALEJANDRA; GONANO L; LASCANO, ELENA; MATTIAZZI, ALICIA

Beijing

Congreso; IUPS 2022; 2022

International Union of Physiological Sciences

Mechanical dysfunction and arrhythmias are a leading cause of morbidity and mortality worldwide, and it is now well established that one of the mechanisms that trigger ventricular arrhythmias is initiated at the cellular level by spontaneous Ca2+ release (Ca2+ sparks) from the sarcoplasmic reticulum (SR). These Ca2+ sparks can multiply and propagate as regenerative Ca2+ waves that travel through the cytosol and force the forward mode of the electrogenic Na+/Ca2+ exchanger (NCX) (depolarizing current). Spontaneous SR-Ca2+ releases occur under conditions in which SR-Ca2+ load exceeds a threshold that is largely determined by the state of the ryanodine receptors (RyR2). Activation of Ca2+?calmodulin-dependent protein kinase II (CaMKII) during reperfusion phosphorylates RyR2 (increasing SR-Ca2+ leak) and phospholamban (PLN) (increasing SR-Ca2+uptake). This scenario is one of the known triggers of reperfusion arrhythmias. It is well known also, that RyR2 point mutations render the channel more prone to spontaneous SR Ca2+ release during adrenergic stimulation. We and others have described that RyR2 phosphorylation by CaMKII at the Ser2814 site is associated with SR Ca2+ leak and arrhythmogenesis in cardiac pathologies of different etiologies. These results define the crucial role of RyR2 altered activity on triggered arrhythmias. In contrast, the effect of increasing SR Ca2+ uptake on cardiac triggered events is controversial about whether the increase in SR Ca2+uptake, which has been shown to be a useful therapy to revert depressed cardiac contractility in human and experimental heart failure, is protective against Ca2+ triggered arrhythmias or exacerbates them. Indeed, either the increase or decrease of SR Ca2+ uptake has led to contradictory results. These conflicting results may rest, at least in part, in the opposite effects inherent to the augmented cytosolic SR Ca2+ uptake, wherein increasing the rate of SR Ca2+ uptake would reduce cytosolic Ca2+ overload (lower risk of cardiac arrhythmias), but at the same time it increases SR Ca2+ content (favoring RyR2 Ca2+ sensitization, and hence diastolic SR Ca2+ leak). Coexistence of increased SR-Ca2+ uptake with RyR2 sensitization might exacerbate this situation. SR Ca2+ uptake and release are highly regulated processes. Therefore, with the aim of elucidating the relative role of RyR2 and PLN phosphorylation in the seesaw game of arrhythmias, we developed a series of experiments which include the use of mutant mice with Ser2814 of RyR2 mutated to aspartate (S2814D) or alanine (S2814A), PLN knockout (PLNKO), and PLNKO crossbred with S2814D or S2814A (SDKO and SAKO, respectively).