Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers

• Published in: Cell reports (Cambridge) 2021-07, Vol.36 (4), p.109448-109448, Article 109448
• Main Authors: Koch, Daniel, Alexandrovich, Alexander, Funk, Florian, Kho, Ay Lin, Schmitt, Joachim P., Gautel, Mathias
• Format: Article
• Language: English
• Subjects: Animals; bistability; Buffers; calcium handling; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; cardiac arrhythmias; cardiomyocytes; Gene Regulatory Networks; HEK293 Cells; Humans; hysteresis; Models, Biological; Mutation - genetics; non-linear dynamics; oligomerization; Phosphorylation; Protein Multimerization; Rats; Rats, Wistar; Receptors, Adrenergic, beta - metabolism; Signal Transduction; signaling networks; systems biology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109448

Phospholamban (PLN) is an important regulator of cardiac calcium handling due to its ability to inhibit the calcium ATPase SERCA. β-Adrenergic stimulation reverses SERCA inhibition via PLN phosphorylation and facilitates fast calcium reuptake. PLN also forms pentamers whose physiological significance has remained elusive. Using mathematical modeling combined with biochemical and cell biological experiments, we show that pentamers regulate both the dynamics and steady-state levels of monomer phosphorylation. Substrate competition by pentamers and a feed-forward loop involving inhibitor-1 can delay monomer phosphorylation by protein kinase A (PKA), whereas cooperative pentamer dephosphorylation enables bistable PLN steady-state phosphorylation. Simulations show that phosphorylation delay and bistability act as complementary filters that reduce the effect of random fluctuations in PKA activity, thereby ensuring consistent monomer phosphorylation and SERCA activity despite noisy upstream signals. Preliminary analyses suggest that the PLN mutation R14del could impair noise filtering, offering a new perspective on how this mutation causes cardiac arrhythmias. [Display omitted] •A dynamical systems model of the PLN signaling network is developed•PLN pentamers enable low-pass filtering (LPF) by competing with PLN monomers•PLN pentamers promote the emergence of bistable PLN phosphorylation•LPF and bistability filter out simulated signal noise in the β-adrenergic pathway While phosphorylation of phospholamban (PLN) is crucial to improve heart function during the β-adrenergic “fight-or-flight” response, the role of PLN pentamers in this context is unclear. By integrating mathematical and experimental approaches, Koch et al. find that PLN pentamers provide complex information-processing capabilities to ensure a consistent phosphorylation response.