150 Chapter 7 ABSTRACT Phospholamban (PLN) encodes for a transmembrane sarcoplasmic reticulum (SR) phosphoprotein and is crucial in the regulation of calcium cycling in cardiomyocytes by interacting with the calcium pump sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA2a). The deletion of amino acid arginine 14 in the cardiac-enriched protein phospholamban (PLNR14del) potentially leads to a super-inhibitory effect towards SERCA2a, causing disturbed calcium handling and decreased contractility in cardiomyocytes. However, the functional consequences of this mutation and the mechanisms underlying PLN-R14del cardiomyopathy remain poorly understood. The purpose of this systematic review is to summarize the research studies conducted on understanding the molecular mechanisms causing PLNR14del cardiomyopathy. This review will emphasize the impact that the discovery of PLNR14del had on fueling insights into the basic biology of calcium handling, protein toxicity, metabolism, and fibrosis, and reinforce the idea that PLN is a crucial dynamic regulator of SERCA2a that contributes to the speed and force of calcium-driven muscle contraction. Finally, the elucidation of the mechanisms involved in cardiomyopathy onset and progression from this causative gene will lead to the development of novel therapeutic agents, which were summarized here.
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