Molecular Noise-Filtering in the β-adrenergic Signaling Network by Phospholamban Pentamers

Daniel Koch, Alex Alexandrovich, Florian Funk, Ay Lin Kho, Joachim P. Schmitt, Mathias Gautel

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.
Original languageEnglish
Article number109448
Pages (from-to)109448
JournalCell Reports
Volume36
Issue number4
DOIs
Publication statusPublished - 27 Jul 2021

Keywords

  • Systems Biology
  • Oligomerization
  • Phosphorylation
  • Signaling networks
  • Cardiomyocytes
  • Calcium handling
  • Cardiac arrhythmias
  • Non-linear dynamics
  • Bistability
  • Hysteresis

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