Determination of CaMKII and PKA role in PLN R14del functional phenotype
Abstract
Phospholamban (PLN) is a 52-amino acid tail-anchored transmembrane protein and an essential regulator in the cardiac excitation-contraction coupling (ECC) involved in the regulation of the Sarcoendoplasmatic Reticulum Ca2+-ATPase 2a (SERCA2a) pump. SERCA2a is a transmembrane pump primarily responsible for Ca2+ reuptake from the cytosol into the Sarcoendoplasmatic Reticulum (SER) lumen of skeletal and cardiac muscle cells during ECC. PLN regulates SERCA2a in a phosphorylation-dependent manner: when PLN is unphosphorylated, it binds to SERCA2a regulating its activity and PLN phosphorylation releases this binding. The exact mechanism of the PLN regulation to SERCA2a is not fully understood but it is known that PLN phosphorylation is a crucial regulatory mechanism that modulates SERCA2a function in Ca²⁺ handling. PLN can be phosphorylated at serine 16 (S16) by protein kinase A (PKA) in response to β-adrenergic stimulation and at threonine 17 (T17) by Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in response to Ca2+overload. Several disease-associated mutations in the PLN gene have been identified in humans. The deletion of arginine 14 (R14 Δ) of PLN is most prevalent in the Netherlands and Northwestern Europe. PLN R14 Δ is the focus of our study and is associated with dilated and/or arrhythmogenic cardiomyopathy. PLN R14 Δ cardiomyopathy is typically characterized in human carriers by “ECG abnormalities, including low QRS-potentials and inverted T-waves in precordial…
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