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

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

doi:10.1016/j.celrep.2021.109448

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Journal: Cell Reports	Publication Date: Jul 1, 2021
Citations: 7	License type: cc-by

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SummaryPhospholamban (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.

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Calcium (Ca2+) currents determine contraction and relaxation of the heart at the cellular level: high Ca2+ concentrations enable sarcomeric contraction, whereas low Ca2+ concentrations lead to relaxation (Bers, 2002; Eisner et al, 2017)
Pentamers are moderate and slow monomer buffers in vitro The predominant paradigm is that PLN pentamers are a storage or buffering reservoir for monomers (Figure 1A) (MacLennan and Kranias, 2003; Becucci et al, 2009; Kranias and Hajjar, 2012; Vostrikov et al, 2013)
To keep our analysis focused on the regulation of PLN phosphorylation in the context of b-adrenergic stimulation, we treated the concentration of active protein kinase A (PKA) at the sarcoplasmic reticulum (SR) as a model input parameter and omitted processes upstream of PKA and downstream of PLN (e.g., sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity, Ca2+handling)

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Calcium (Ca2+) currents determine contraction and relaxation of the heart at the cellular level: high Ca2+ concentrations enable sarcomeric contraction, whereas low Ca2+ concentrations lead to relaxation (Bers, 2002; Eisner et al, 2017). Phosphorylation of PLN at Ser by protein kinase A (PKA) reverses SERCA inhibition in response to b-adrenergic stimulation, thereby accelerating Ca2+ removal and cardiomyocyte relaxation (Tada et al, 1975; Kranias and Solaro, 1982; Lindemann et al, 1983; MacLennan and Kranias, 2003; Kranias and Hajjar, 2012) This constitutes an important mechanism to adapt cardiac output to increasing demand and is an integral part of the b-adrenergic ‘‘fight-orflight’’ response (Simmerman and Jones, 1998; MacLennan and Kranias, 2003; Kranias and Hajjar, 2012). Multiple mutations in the PLN gene have been discovered in the past two decades, most of which cause severe forms of cardiomyopathy and lead to cardiac arrhythmias or heart failure (Schmitt et al, 2003, 2009; Haghighi et al, 2006; Medeiros et al, 2011; Yost et al, 2019)

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