Specificity of NHERF1 regulation of GPCR signaling and function in human airway smooth muscle

Na+/H+ exchanger regulatory factor 1 (NHERF1; also known as ezrin-radixin-moesin–binding phosphoprotein 50) is a PSD-95, disc large, zona occludens-1 adapter that acts as a scaffold for signaling complexes and cytoskeletal-plasma membrane interactions. NHERF1 is crucial to β-2-adrenoceptor (β2AR)-mediated activation of CFTR in epithelial cells, and NHERF1 has been proposed to mediate the recycling of internalized β2AR back to the cell membrane. In the current study, we assessed the role of NHERF1 in regulating cAMP-mediated signaling and immunomodulatory functions in airway smooth muscle (ASM). NHERF1 knockdown attenuated the induction of (protein kinase A) phospho–vasodilator-stimulated phosphoprotein (p-VASP) by isoproterenol (ISO), prostaglandin E2 (PGE2), or forskolin (FSK) as well as the induction of p–heat shock protein 20 after 4 h of stimulation with ISO and FSK. NHERF1 knockdown fully abrogated the ISO-, PGE2-, and FSK-induced IL-6 gene expression and cytokine production without affecting cAMP-me...