β‐Agonists regulate Na,K‐ATPase via novel MAPK/ERK and rapamycin‐sensitive pathways

We studied whether the beta-adrenergic agonist, isoproterenol (ISO), regulates Na,K-ATPase in alveolar epithelial cells (AEC) via a mitogen-activated protein kinase (MAPK)/extracellular signaling related kinase (ERK) dependent pathway. ISO increased ERK activity in AEC by 10 min via a beta-adrenergic receptor, protein kinase A (PKA)-dependent mechanism. Activation of the MAPK pathway by ISO, resulted in increased Na,K-ATPase beta1 and alpha1 subunit protein abundance in whole cell lysates, which resulted in functional Na, K-ATPases at the basolateral membranes. ISO did not change the alpha1 or beta1 mRNA steady state levels, but rapamycin, the inhibitor of the mammalian target of rapamycin, also blocked the ISO-mediated increase in Na,K-ATPase total protein abundance, suggesting a posttranscriptional regulation. We conclude that ISO, regulates the Na,K-ATPase in AEC via PKA, ERK and rapamycin-sensitive mechanisms.