{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhospholamban (PLN) is a central regulator of cardiac contractility that functions primarily by binding to the sarcoplasmic reticulum Ca²⁺‐ATPase (SERCA) to modulate intracellular calcium uptake and, thereby, the cycle of muscle contraction and relaxation. Biophysical and structural studies have demonstrated that PLN exists as an oligomer—most notably as a pentamer—with a dynamic cytoplasmic domain that undergoes a conformational order–disorder transition upon phosphorylation (e.g., via protein kinase A). This phosphorylation relieves its inhibitory effect on SERCA, ensuring proper calcium re‐sequestration during diastole. In addition, PLN is known to form dynamic complexes with other regulatory proteins (such as S100A1 and sarcolipin), and its membrane topology is sensitive to the lipid environment, a factor that fine‐tunes SERCA activity and myocardial Ca²⁺ homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in PLN can profoundly alter this finely tuned regulatory mechanism, leading to various forms of cardiomyopathy and arrhythmias. Several disease‐causing mutations—such as missense substitutions at arginine 9 (R9C) and deletion of arginine 14 (R14del)—impair normal phosphorylation dynamics and may alter the conformational equilibrium of PLN, resulting in either loss‐of‐function or dominant negative inhibition of SERCA. Genetic and genome‐wide association studies have further implicated variants near the PLN locus in prolongation of the QT interval, modification of heart rate, and predisposition to dilated, arrhythmogenic, and hypertrophic cardiomyopathies. Biochemical and structural modeling studies have underscored the importance of specific residues and hydrophobic balance within PLN’s cytoplasmic domain for its regulatory interaction with SERCA, as well as its capacity to form stable pentameric assemblies. Such deleterious mutations, which have been identified across diverse populations and correlated with both contractile dysfunction and myocardial remodeling, highlight the critical role of PLN in maintaining normal Ca²⁺ cycling and cardiac function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in modulating SERCA, PLN is embedded within a broader network of regulatory interactions that extend to both cardiac and skeletal muscle tissues, with implications for novel therapeutic strategies. Studies in human engineered cardiomyocytes and stem cell–derived models have underscored how altered PLN expression can impact β-adrenergic responsiveness and contractile reserve. In parallel, investigations into PLN’s interplay with other modulators—as evidenced by its coassociation with sarcolipin in skeletal muscle and its influence on myocardial fibrosis in arrhythmogenic cardiomyopathy—suggest that targeting aberrant PLN signaling could represent a promising avenue for intervention in heart failure and arrhythmia-prone cardiomyopathies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chikashi Toyoshima, Michio Asahi, Yuji Sugita, et al. 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