164 Chapter 7 Figure 2: Regulation of calcium uptake and contractility in PLN wildtype versus PLN-R14del. In PLN wildtype, PLN phosphorylation is regulated by protein kinase A (PKA) at serine 16 and/or Ca2+/calmodulindependent protein kinase II (CaMKII) at the threonine 17 residue. The type 1 protein phosphatase (PP1) dephosphorylation of PLN, thereby inhibiting SERCA2a’s affinity for Ca2+. The cytosolic Ca2+ binds to troponin, causing conformational changes in the sarcomere, which leads to the interaction of thick and thin filaments of the sarcomere and muscle contraction. In PLN-R14del, the R-R-X-S motif crucial for the phosphorylation of Ser16 by PKA is disrupted, thereby limiting the extent to which SERCA2a inhibition can be reversed. Hypothetically, the enhanced cytosolic Ca2+ levels result in defective muscle contraction and/or relaxation, which is the cause of various muscle diseases. PLN Monomer vs Pentamers PLN exists in a dynamic equilibrium between its monomeric and pentameric form, which is influenced by its phosphorylation state. While PLN monomers seem to be important for the reversible inhibition of SERCA, the function of PLN pentamer has not been fully elucidated and has been proposed to function as 1) storage for active monomers127, 2) an ion channel128, and/ or 3) a SERCA binding partner required for the regulation of cardiac contractility129. Indeed, in both synthetic and cell membranes, PLN was found to form pentamers to regulate the concentration of active monomers available to bind SERCA and keep its function within a physiological window.130 Other studies suggested that the pentamer structure displays a channel-forming architecture that could allow the passage of small ions such as Ca2+131 or Cl− 132. However, both electrochemical measurements and free energy calculations provide strong evidence that PLN, whether in bellflower or pinwheel configurations, does not conduct Ca2+ or Cl− ions.133 A recent study showed that PLN pentamers are not entirely passive but interact with SERCA in a 1:1 complex, influencing cardiomyocyte contractility and PLN phosphorylation dynamics.134 This interaction with SERCA2a appears to act as buffers, fine-tuning SERCA turnover and regulation via monomeric PLN.135,136 As a consequence,
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