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AICAR decreases the activity of two distinct amiloride-sensitive Na⁺-permeable channels in H441 human lung epithelial cell monolayers

¹Centre for Ion Channels and Cell Signalling, Division of Basic Medical Sciences, Saint George's, University of London, London; and ²School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom

Submitted 18 June 2008 ; accepted in final form 19 August 2008

Transepithelial transport of Na⁺ across the lung epithelium via amiloride-sensitive Na⁺ channels (ENaC) regulates fluid volume in the lung lumen. Activators of AMP-activated protein kinase (AMPK), the adenosine monophosphate mimetic AICAR, and the biguanide metformin decreased amiloride-sensitive apical Na⁺ conductance (G_Na+) in human H441 airway epithelial cell monolayers. Cell-attached patch-clamp recordings identified two distinct constitutively active cation channels in the apical membrane that were likely to contribute to G_Na+: a 5-pS highly Na⁺ selective ENaC-like channel (HSC) and an 18-pS nonselective cation channel (NSC). Substituting NaCl with NMDG-Cl in the patch pipette solution shifted the reversal potentials of HSC and NSC, respectively, from +23 mV to –38 mV and 0 mV to –35 mV. Amiloride at 1 µM inhibited HSC activity and 56% of short-circuit current (I_sc), whereas 10 µM amiloride partially reduced NSC activity and inhibited a further 30% of I_sc. Neither conductance was associated with CNG channels as there was no effect of 10 µM pimoside on I_sc, HSC, or NSC activity, and 8-bromo-cGMP (0.3–0.1 mM) did not induce or increase HSC or NSC activity. Pretreatment of H441 monolayers with 2 mM AICAR inhibited HSC/NSC activity by 90%, and this effect was reversed by the AMPK inhibitor Compound C. All three ENaC proteins were identified in the apical membrane of H441 monolayers, but no change in their abundance was detected after treatment with AICAR. In conclusion, activation of AMPK with AICAR in H441 cell monolayers is associated with inhibition of two distinct amiloride-sensitive Na⁺-permeable channels by a mechanism that likely reduces channel open probability.

5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; AMP-activated protein kinase; ENaC

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