162 Chapter 7 of developing VT. They may also pave the way for future research to explore the potential therapeutic strategies for managing apical mechanical alterations in PLN-R14del carriers to prevent the development of VT. However, it is essential to determine the optimal frequency and timing of follow-up echocardiograms to monitor changes in mechanical behavior and adjust preventive strategies will be crucial for effective clinical management. Recent studies in mouse models of PLN-R14del disease revealed the ability to detect abnormal cardiac function and increased arrhythmogenic vulnerability in pre-symptomatic hPLN-R14del mice, which reflect similarities to pre-symptomatic PLN-R14del patients.62,73,76,90 The study by Dave et al. is particularly exciting, as it demonstrates the potential therapeutic benefits of allele-specific disruption of the PLN-R14del mutation using in vivo AAV9/CRISPR-Cas9. The ability to improve cardiac function and reduce VT susceptibility to wild-type levels is a significant achievement and offers new hope for patients in the early stages of PLN-R14del disease. These studies suggest that the combination of animal models of PLN-R14del disease and emerging therapeutic strategies, such as allele-specific disruption of the PLN-R14del mutation using genome editing approaches, has the potential to revolutionize the treatment of this disease and possibly other inherited cardiomyopathies. Super-inhibition of SERCA2a Mechanistically, the arginine residues (Arg9, Arg13, and Arg14) of PLN interact transiently with SERCA-Glu606, while for the phosphorylated PLN, the phosphate group at Ser16 forms strong interactions with SERCA-Arg604 and SERCA-Lys605.117 This dynamic interplay is essential for the regulation of SERCA2a activity. However, the R14del mutation disrupts the R-R-X-S motif crucial for the phosphorylation of Ser16 by PKA, thereby limiting the extent to which SERCA2a inhibition can be reversed.118 In addition, R14del appears to disrupt the mutant protein’s coil domain, an essential structure that provides structural flexibility to PLN, enabling conformational changes associated with PLN phosphorylation and its association with SERCA2a.36,96,119 Consequently, in the context of PLN-R14del-related disease, this mutation is believed to exert a constitutive inhibitory effect on SERCA2a, even when phosphorylated by PKA and activated CaMKII. This persistent inhibition leads to increased cytosolic Ca2+, which can have several consequences, including the phosphorylation of the S2814 site of the ryanodine receptor 2 (RyR2), resulting in the release of more calcium from the sarcoplasmic reticulum into the cytosol, which can contribute to disturbances in cardiac function and potentially lead to arrhythmias or contractile dysfunction.120 The concept of “super-inhibition” of SERCA2a by PLN-R14del has been substantiated by previous research findings. Haghighi et al. demonstrated the super-inhibition of SERCA activity in both co-transfected HEK-293 cells and transgenic mice overexpressing the mutation. Importantly, they observed that the dominant effect of the mutation could not be completely removed by phosphorylation mediated by PKA.121 Furthermore, Vafiadaki et al. confirmed this increased inhibitory effect
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