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This Article Full Text Full Text (PDF) All Versions of this Article: 586/18/4541    most recent jphysiol.2008.158253v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Mace, O. J. Articles by Baines, D. L. PubMed PubMed Citation Articles by Mace, O. J. Articles by Baines, D. L. Related Collections Respiratory

¹ Division of Basic Medical Sciences, St George's University of London, Cranmer Terrace, London SW17 0RE, UK
² University of Brighton, Pharmacy and Biomolecular Sciences, Cockcroft, Brighton BN2 4GJ, UK

Changes in amiloride-sensitive epithelial Na⁺ channel (ENaC) activity (NP_o) in the lung lead to pathologies associated with dysregulation of lung fluid balance. UTP activation of purinergic receptors and hydrolysis of PIP₂ via activation of phospholipase C (PLC) or AICAR activation of AMP-activated protein kinase (AMPK) inhibited amiloride-sensitive Na⁺ transport across human H441 epithelial cell monolayers. Neither treatment altered , β or ENaC subunit abundance (N) in the apical membrane indicating that the mechanism of inhibition was via a change in channel open state probability (P_o). We found that UTP depleted PIP₂ abundance in the apical membrane whilst activation of AMPK prevented the binding of β and ENaC subunits to PIP_2. The association of PIP₂ with the ENaC subunits is required to maintain channel activity via P_o. Thus, these data show for the first time that AICAR activation of AMPK inhibits Na⁺ transport via a mechanism that perturbs the PIP₂–ENaC channel interaction to alter P_o. In addition, we show that dissociation of PIP₂ from ENaC together with activation of AMPK further reduced Na⁺ transport by a secondary effect that correlated with ENaC subunit internalization. Thus, when PIP₂–ENaC subunit interactions were compromised, ENaC protein retrieval was initiated, indicating that AMPK can modulate ENaC P_o and N.

(Received 13 June 2008; accepted after revision 24 July 2008; first published online 31 July 2008)
Corresponding author O. J. Mace: Division of Basic Medical Sciences, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.  Email: omace{at}sgul.ac.uk

This article has been cited by other articles:

				A. P. Albert, A. M. Woollhead, O. J. Mace, and D. L. Baines AICAR decreases the activity of two distinct amiloride-sensitive Na+-permeable channels in H441 human lung epithelial cell monolayers Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L837 - L848. [Abstract] [Full Text] [PDF]