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Vasoactive intestinal peptide (VIP) is a topical airway gland secretagogue regulating fluid secretions, primarily by stimulating cystic fibrosis transmembrane conductance regulator (CFTR)-dependent chloride secretion that contributes to the airways innate defense mechanism. We previously reported that prolonged VIP stimulation of pituitary adenylate cyclase-activating peptide receptors (VPAC1) in airway cells enhances CFTR function by increasing its membrane stability. In the present study, we identified the key effectors in the VIP signaling cascade in the human bronchial serous cell line Calu-3. Using immunocytochemistry and in situ proximity ligation assays, we found that VIP stimulation increased CFTR membrane localization by promoting its colocalization and interaction with the scaffolding protein Na(+)/H(+) exchange factor 1 (NHERF1), a PDZ protein known as a positive regulator for CFTR membrane localization. VIP stimulation also increased phosphorylation, by protein kinase Cε of the actin-binding protein complex ezrin/radixin/moesin (ERM) and its interaction with NHERF1 and CFTR complex. On the other hand, it reduced intracellular CFTR colocalization and interaction with CFTR associated ligand, another PDZ protein known to compete with NHERF1 for CFTR interaction, inducing cytoplasmic retention and lysosomal degradation. Reducing NHERF1 or ERM expression levels by specific siRNAs prevented the VIP effect on CFTR membrane stability. Furthermore, iodide efflux assays confirmed that NHERF1 and P-ERM are necessary for VIP regulation of the stability and sustained activity of membrane CFTR. This study shows the cellular mechanism by which prolonged VIP stimulation of airway epithelial cells regulates CFTR-dependent secretions.

Titel:	VIP regulates CFTR membrane expression and function in Calu-3 cells by increasing its interaction with NHERF1 and P-ERM in a VPAC1- and PKCε-dependent manner.
Autor/in / Beteiligte Person:	Alshafie, W ; Chappe, FG ; Li, M ; Anini, Y ; Chappe, VM
Zeitschrift:	American journal of physiology. Cell physiology, Jg. 307 (2014-07-01), Heft 1, S. C107
Veröffentlichung:	Bethesda, Md. : American Physiological Society,, 2014
Medientyp:	academicJournal
ISSN:	1522-1563 (electronic)
DOI:	10.1152/ajpcell.00296.2013
Schlagwort:	Adaptor Proteins, Signal Transducing Bronchi cytology Carrier Proteins metabolism Cell Line Golgi Matrix Proteins Humans Membrane Transport Proteins Phosphoproteins genetics Phosphorylation Protein Binding RNA Interference Signal Transduction Sodium-Hydrogen Exchangers genetics Time Factors Transfection Bronchi enzymology Cystic Fibrosis Transmembrane Conductance Regulator metabolism Cytoskeletal Proteins metabolism Epithelial Cells enzymology Membrane Proteins metabolism Microfilament Proteins metabolism Phosphoproteins metabolism Protein Kinase C-epsilon metabolism Receptors, Vasoactive Intestinal Polypeptide, Type I metabolism Sodium-Hydrogen Exchangers metabolism Vasoactive Intestinal Peptide metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Am J Physiol Cell Physiol] 2014 Jul 01; Vol. 307 (1), pp. C107-19. <i>Date of Electronic Publication: </i>2014 Apr 30. MeSH Terms: Bronchi / enzymology ; Cystic Fibrosis Transmembrane Conductance Regulator / metabolism ; Cytoskeletal Proteins / metabolism ; Epithelial Cells / enzymology ; Membrane Proteins / metabolism ; Microfilament Proteins / metabolism ; Phosphoproteins / metabolism ; Protein Kinase C-epsilon / metabolism ; Receptors, Vasoactive Intestinal Polypeptide, Type I / metabolism ; Sodium-Hydrogen Exchangers / metabolism ; Vasoactive Intestinal Peptide / *metabolism ; Adaptor Proteins, Signal Transducing ; Bronchi / cytology ; Carrier Proteins / metabolism ; Cell Line ; Golgi Matrix Proteins ; Humans ; Membrane Transport Proteins ; Phosphoproteins / genetics ; Phosphorylation ; Protein Binding ; RNA Interference ; Signal Transduction ; Sodium-Hydrogen Exchangers / genetics ; Time Factors ; Transfection Contributed Indexing: Keywords: Na+/H+ exchange factor 1; cystic fibrosis associated ligand; cystic fibrosis transmembrane conductance regulator; ezrin/radixin/moesin; protein kinase C epsilon; vasoactive intestinal peptide Substance Nomenclature: 0 (Adaptor Proteins, Signal Transducing) ; 0 (CFTR protein, human) ; 0 (Carrier Proteins) ; 0 (Cytoskeletal Proteins) ; 0 (GOPC protein, human) ; 0 (Golgi Matrix Proteins) ; 0 (Membrane Proteins) ; 0 (Membrane Transport Proteins) ; 0 (Microfilament Proteins) ; 0 (Phosphoproteins) ; 0 (Receptors, Vasoactive Intestinal Polypeptide, Type I) ; 0 (Sodium-Hydrogen Exchangers) ; 0 (ezrin) ; 0 (sodium-hydrogen exchanger regulatory factor) ; 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) ; 144131-77-1 (moesin) ; 144517-21-5 (radixin) ; 37221-79-7 (Vasoactive Intestinal Peptide) ; EC 2.7.11.13 (PRKCE protein, human) ; EC 2.7.11.13 (Protein Kinase C-epsilon) Entry Date(s): Date Created: 20140503 Date Completed: 20140828 Latest Revision: 20201209 Update Code: 20240513

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VIP regulates CFTR membrane expression and function in Calu-3 cells by increasing its interaction with NHERF1 and P-ERM in a VPAC1- and PKCε-dependent manner.