Phospholemman is a negative feed-forward regulator of Ca2+ in β-adrenergic signaling, accelerating β-adrenergic inotropy

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 Ca2+ 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) Ca2+ clamps, we identify an effect of PLM phosphorylation on SR unloading as the key mechanism by which PLM confers cytosolic Ca2+ 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.

Graphical abstract1.SR Ca2+ load specifies the size of Ca2+ transients during CICR.2.PLB increases SR load by biasing diastolic Ca2+ extrusion toward SERCA.3.PLM decreases SR load by driving Na+ extrusion and biasing diastolic Ca2+ extrusion toward NCX.4.Ca2+ adaptation occurs because Na+/K+ dynamics lag behind SERCA dynamics.5.Receptor desensitization weakly contributes to Ca2+ adaptation, highlighting a negative feed-forward loop formed by PLB and PLM. This negative feed-forward network motif accelerates β-adrenergic inotropy.Figure optionsDownload full-size imageDownload high-quality image (178 K)Download as PowerPoint slideHighlights► PLM confers cytosolic Ca2+ adaptation via manipulation of SR load. ► PLM and PLB form a negative feed-forward loop in β-adrenergic signaling. ► PLM phosphorylation accelerates β-adrenergic stimulation enhanced contractility. ► PLM is therefore a fundamentally important part of the fight-or-flight response.