Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers
Summary: 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 si...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721008652 |
| _version_ | 1818573889324711936 |
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| author | Daniel Koch Alexander Alexandrovich Florian Funk Ay Lin Kho Joachim P. Schmitt Mathias Gautel |
| author_facet | Daniel Koch Alexander Alexandrovich Florian Funk Ay Lin Kho Joachim P. Schmitt Mathias Gautel |
| author_sort | Daniel Koch |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-15T00:18:56Z |
| format | Article |
| id | doaj.art-20c61edb341c47519eb009134f570dcc |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-15T00:18:56Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-20c61edb341c47519eb009134f570dcc2022-12-21T22:42:22ZengElsevierCell Reports2211-12472021-07-01364109448Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamersDaniel Koch0Alexander Alexandrovich1Florian Funk2Ay Lin Kho3Joachim P. Schmitt4Mathias Gautel5Randall Centre for Cell and Molecular Biophysics, King’s College London, SE1 1UL London, UK; Corresponding authorRandall Centre for Cell and Molecular Biophysics, King’s College London, SE1 1UL London, UKInstitute of Pharmacology and Clinical Pharmacology, and Cardiovascular Research Institute Düsseldorf (CARID), University Hospital Düsseldorf, 40225 Düsseldorf, GermanyRandall Centre for Cell and Molecular Biophysics, King’s College London, SE1 1UL London, UKInstitute of Pharmacology and Clinical Pharmacology, and Cardiovascular Research Institute Düsseldorf (CARID), University Hospital Düsseldorf, 40225 Düsseldorf, GermanyRandall Centre for Cell and Molecular Biophysics, King’s College London, SE1 1UL London, UKSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721008652systems biologyoligomerizationphosphorylationsignaling networkscardiomyocytescalcium handling |
| spellingShingle | Daniel Koch Alexander Alexandrovich Florian Funk Ay Lin Kho Joachim P. Schmitt Mathias Gautel Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers Cell Reports systems biology oligomerization phosphorylation signaling networks cardiomyocytes calcium handling |
| title | Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers |
| title_full | Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers |
| title_fullStr | Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers |
| title_full_unstemmed | Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers |
| title_short | Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers |
| title_sort | molecular noise filtering in the β adrenergic signaling network by phospholamban pentamers |
| topic | systems biology oligomerization phosphorylation signaling networks cardiomyocytes calcium handling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721008652 |
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