163 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 by reporting increased binding of PLN-R14del to SERCA2a and HAX-1, a protein, which binds directly to PLN, modulating its activity either by enhancing its inhibitory action on SERCA2a. This strengthened interaction intensifies the inhibitory effect of PLN-R14del on SERCA2a.122 As a result, calcium reuptake is further impaired, leading to increased release of Ca2+ from the SR into the cytosol. These disruptions in calcium handling can trigger various cardiac events, including after-contractions, transient inward currents, and arrhythmogenic delayed afterdepolarizations (DADs).123–125 However, it's important to note that some studies have reported contradictory findings regarding the influence of PLN-R14del on SERCA2a. For instance, Badone et al. observed increased SERCA2a function in PLN-R14del-hiPSC-CMs due to a loss of PLN’s inhibitory function.126 Furthermore, a recent preprint study from the same research group demonstrated hyperdynamic Ca2+ handling and reduced SERCA2a inhibition by PLN-R14del in ventricular cardiomyocytes from 8-12 weeks-old transgenic mice.103 In isolated CMs from homozygous R14del mice, an enhanced calcium reuptake was observed108, which is in line with the publications above on altered calcium reuptake by mutant PLN-R14del. These findings challenge the notion of super-inhibition of SERCA2a, which could have explained the previously observed ACM phenotype. Nevertheless, the constitutively unrestrained function of SERCA2a may, in the long term, negatively impact myocyte function as well. In summary, the PLN-R14del mutation's effects on SERCA2a function remain a subject of debate and ongoing research. These findings imply that factors beyond the super-inhibition of SERCA2a may contribute to the development of PLN-R14del-induced DCM/ACM. Further investigation is needed to fully elucidate the complex mechanisms underlying these conditions in individuals with this genetic mutation.
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