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The phosphorylation of endogenous Nedd4-2 In Na(+)-absorbing human airway epithelial cells.
Eur J Pharmacol. 2014 Jun 05; 732:32-42.EJ

Abstract

Neural precursor cell expressed, developmentally down-regulated protein 4-2 (Nedd4-2) mediates the internalisation / degradation of epithelial Na(+) channel subunits (α-, β- and γ-ENaC). Serum / glucocorticoid inducible kinase 1 (SGK1) and protein kinase A (PKA) both appear to inhibit this process by phosphorylating Nedd4-2-Ser(221), -Ser(327) and -Thr(246). This Nedd4-2 inactivation process is thought to be central to the hormonal control of Na(+) absorption. The present study of H441 human airway epithelial cells therefore explores the effects of SGK1 and / or PKA upon the phosphorylation / abundance of endogenous Nedd4-2; the surface expression of ENaC subunits, and electrogenic Na(+) transport. Effects on Nedd4-2 phosphorylation/abundance and the surface expression of ENaC were monitored by western analysis, whilst Na(+) absorption was quantified electrometrically. Acutely (20min) activating PKA in glucocorticoid-deprived (24h) cells increased the abundance of Ser(221)-phosphorylated, Ser(327)-phosphorylated and total Nedd4-2 without altering the abundance of Thr(246)-phosphorylated Nedd4-2. Activating PKA under these conditions did not cause a co-ordinated increase in the surface abundance of α-, β- and γ-ENaC and had only a very small effect upon electrogenic Na(+) absorption. Activating PKA (20min) in glucocorticoid-treated (0.2µM dexamethasone, 24h) cells, on the other hand, increased the abundance of Ser(221)-, Ser(327)- and Thr(246)-phosphorylated and total Nedd4-2; increased the surface abundance of α-, β- and γ-ENaC and evoked a clear stimulation of Na(+) transport. Chronic glucocorticoid stimulation therefore appears to allow cAMP-dependent control of Na(+) absorption by facilitating the effects of PKA upon the Nedd4-2 and ENaC subunits.

Authors+Show Affiliations

Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 9SY, UK; Biochemistry Department, Faculty of Medicine, University Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.Biomedical Sciences Research Centre, St Georges University of London, Cranmer Terrace, London, UK.Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 9SY, UK; Wolfson Research Institute, School of Medicine, Pharmacy and Health, Durham University Queen׳s Campus, Stockton on Tees, TS17 6BH, UK. Electronic address: Stuart.wilson@durham.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24657276

Citation

Ismail, Noor A S., et al. "The Phosphorylation of Endogenous Nedd4-2 in Na(+)-absorbing Human Airway Epithelial Cells." European Journal of Pharmacology, vol. 732, 2014, pp. 32-42.
Ismail NA, Baines DL, Wilson SM. The phosphorylation of endogenous Nedd4-2 In Na(+)-absorbing human airway epithelial cells. Eur J Pharmacol. 2014;732:32-42.
Ismail, N. A., Baines, D. L., & Wilson, S. M. (2014). The phosphorylation of endogenous Nedd4-2 In Na(+)-absorbing human airway epithelial cells. European Journal of Pharmacology, 732, 32-42. https://doi.org/10.1016/j.ejphar.2014.03.005
Ismail NA, Baines DL, Wilson SM. The Phosphorylation of Endogenous Nedd4-2 in Na(+)-absorbing Human Airway Epithelial Cells. Eur J Pharmacol. 2014 Jun 5;732:32-42. PubMed PMID: 24657276.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The phosphorylation of endogenous Nedd4-2 In Na(+)-absorbing human airway epithelial cells. AU - Ismail,Noor A S, AU - Baines,Deborah L, AU - Wilson,Stuart M, Y1 - 2014/03/18/ PY - 2013/11/01/received PY - 2014/03/03/revised PY - 2014/03/10/accepted PY - 2014/3/25/entrez PY - 2014/3/25/pubmed PY - 2014/12/15/medline KW - Cellular signalling KW - Epithelial Na(+) channel KW - Protein kinase A KW - Pulmonary Na(+) absorption KW - Serum and glucocorticoid regulated kinase 1 SP - 32 EP - 42 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 732 N2 - Neural precursor cell expressed, developmentally down-regulated protein 4-2 (Nedd4-2) mediates the internalisation / degradation of epithelial Na(+) channel subunits (α-, β- and γ-ENaC). Serum / glucocorticoid inducible kinase 1 (SGK1) and protein kinase A (PKA) both appear to inhibit this process by phosphorylating Nedd4-2-Ser(221), -Ser(327) and -Thr(246). This Nedd4-2 inactivation process is thought to be central to the hormonal control of Na(+) absorption. The present study of H441 human airway epithelial cells therefore explores the effects of SGK1 and / or PKA upon the phosphorylation / abundance of endogenous Nedd4-2; the surface expression of ENaC subunits, and electrogenic Na(+) transport. Effects on Nedd4-2 phosphorylation/abundance and the surface expression of ENaC were monitored by western analysis, whilst Na(+) absorption was quantified electrometrically. Acutely (20min) activating PKA in glucocorticoid-deprived (24h) cells increased the abundance of Ser(221)-phosphorylated, Ser(327)-phosphorylated and total Nedd4-2 without altering the abundance of Thr(246)-phosphorylated Nedd4-2. Activating PKA under these conditions did not cause a co-ordinated increase in the surface abundance of α-, β- and γ-ENaC and had only a very small effect upon electrogenic Na(+) absorption. Activating PKA (20min) in glucocorticoid-treated (0.2µM dexamethasone, 24h) cells, on the other hand, increased the abundance of Ser(221)-, Ser(327)- and Thr(246)-phosphorylated and total Nedd4-2; increased the surface abundance of α-, β- and γ-ENaC and evoked a clear stimulation of Na(+) transport. Chronic glucocorticoid stimulation therefore appears to allow cAMP-dependent control of Na(+) absorption by facilitating the effects of PKA upon the Nedd4-2 and ENaC subunits. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/24657276/The_phosphorylation_of_endogenous_Nedd4_2_In_Na_+__absorbing_human_airway_epithelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(14)00186-1 DB - PRIME DP - Unbound Medicine ER -