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

ABSTRACT: Sympathetic stimulation enhances cardiac contractility by stimulating ?-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 ?-adrenergic inotropy. Here we developed a computational model to clarify PLM's role in the ?-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 ?-adrenergic receptor (?-AR) stimulation. Moreover, we show that phospholamban (PLB) opposes and overtakes these actions on SR load, forming a negative feed-forward loop in the ?-adrenergic signaling cascade. This network motif dominates the negative feedback conferred by ?-AR desensitization and accelerates ?-AR-induced inotropy. Model analysis therefore unmasks key actions of PLM phosphorylation during ?-adrenergic signaling, indicating that PLM is a critical component of the fight-or-flight response.

SUBMITTER: Yang JH 

PROVIDER: S-EPMC3327824 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature