title: Phospholemman is a negative feed-forward regulator of Ca2+ in β-adrenergic signaling, accelerating β-adrenergic inotropy.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA. jhyang@virginia.edu
authors.forename: Jason H
authors.initials: JH
authors.lastname: Yang
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Saucerman
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000502:physiology; D003198:Computer Simulation; D025461:Feedback, Physiological; D006352:Heart Ventricles / Q000166:cytology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012964:Sodium / Q000502:physiology; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011943:Receptors, Adrenergic, beta; D012964:Sodium; D000099211:Phospholamban; C069141:phospholemman