Phospholemman is a negative feed-forward regulator of Ca 2+ in β-adrenergic signaling, accelerating β-adrenergic inotropy

Jason H. Yang, Jeffrey J. Saucerman

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Sympathetic stimulation enhances cardiac contractility by stimulating β-adrenergic signaling and protein kinase A (PKA). Recently, phospholemman (PLM) has emerged as an important PKA substrate capable of regulating cytosolic Ca 2+ transients. However, it remains unclear how PLM contributes to β-adrenergic inotropy. Here we developed a computational model to clarify PLM's role in the β-adrenergic signaling response. Simulating Na + and sarcoplasmic reticulum (SR) Ca 2+ clamps, we identify an effect of PLM phosphorylation on SR unloading as the key mechanism by which PLM confers cytosolic Ca 2+ adaptation to long-term β-adrenergic receptor (β-AR) stimulation. Moreover, we show that phospholamban (PLB) opposes and overtakes these actions on SR load, forming a negative feed-forward loop in the β-adrenergic signaling cascade. This network motif dominates the negative feedback conferred by β-AR desensitization and accelerates β-AR-induced inotropy. Model analysis therefore unmasks key actions of PLM phosphorylation during β-adrenergic signaling, indicating that PLM is a critical component of the fight-or-flight response.

Original languageEnglish (US)
Pages (from-to)1048-1055
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Issue number5
StatePublished - May 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Molecular Biology


  • Computational model
  • Excitation-contraction coupling
  • Na
  • Negative feed-forward
  • Phospholemman
  • β-Adrenergic signaling


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