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

Phospholamban (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.