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

Daniel Koch; Alexander Alexandrovich; Florian Funk; Ay Lin Kho; Joachim P. Schmitt; Mathias Gautel

doi:10.1016/j.celrep.2021.109448

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

Cell Reports ◽

10.1016/j.celrep.2021.109448 ◽

2021 ◽

Vol 36 (4) ◽

pp. 109448

Author(s):

Daniel Koch ◽

Alexander Alexandrovich ◽

Florian Funk ◽

Ay Lin Kho ◽

Joachim P. Schmitt ◽

...

Keyword(s):

Signaling Network ◽

Noise Filtering ◽

Adrenergic Signaling ◽

Molecular Noise

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

10.1101/2020.12.30.424828 ◽

2020 ◽

Author(s):

Daniel Koch ◽

Alexander Alexandrovich ◽

Florian Funk ◽

Joachim P. Schmitt ◽

Mathias Gautel

Keyword(s):

Steady State ◽

Calcium Handling ◽

Noise Filtering ◽

Adrenergic Stimulation ◽

Molecular Noise ◽

Plasmic Reticulum ◽

Important Regulator ◽

Steady State Levels ◽

New Perspective ◽

Random Fluctuations

AbstractPhospholamban (PLN) is an important regulator of calcium handling in cardiomyocytes due to its ability to inhibit the sarco(endo)plasmic reticulum 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 biochemical experiments and mathematical modeling, 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). Steady-state phosphorylation of PLN is predicted to be bistable due to cooperative dephosphorylation of pentamers. Both effects act as complementary noise-filters which can reduce the effect of random fluctuations in PKA activity. Pentamers thereby ensure consistent monomer phosphorylation and SERCA activity in spite of 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.

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The role of stochastic sequestration dynamics for intrinsic noise filtering in signaling network motifs

10.1101/278929 ◽

2018 ◽

Author(s):

Debdas Paul ◽

Nicole Radde

Keyword(s):

Intrinsic Noise ◽

Signaling Network ◽

Noise Filtering ◽

Network Motifs ◽

Time Varying ◽

Dynamic Noise ◽

Output Fluctuations ◽

Upstream Kinase ◽

Biological Context

AbstractThe relation between design principles of signaling network motifs and their robustness against intrinsic noise still remains illusive. In this work we investigate the role of cascading for coping with intrinsic noise due to stochasticity in molecular reactions. We use stochastic approaches to quantify fluctuations in the terminal kinase of phosphorylation-dephosphorylation cascade motifs and demonstrate that cascading highly affects these fluctuations. We show that this purely stochastic effect can be explained by time-varying sequestration of upstream kinase molecules. In particular, we discuss conditions on time scales and parameter regimes which lead to a reduction of output fluctuations. Our results are put into biological context by adapting rate parameters of our modeling approach to biologically feasible ranges for general binding-unbinding and phosphorylation-dephosphorylation mechanisms. Overall, this study reveals a novel role of stochastic sequestration for dynamic noise filtering in signaling cascade motifs.

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