Activation of AMPK with phenformin (5mM for 1hour) decreased amiloride sensitive transepithelial Na⁺ transport (I_amiloride ) and apical Na⁺ conductance via ENaC (G_Na+ ) by ~50% across H441 airway epithelial cell monolayers. AMPK could decrease open probability (Po) and/or channel number (N). Insertion of ENaC can be stimulated by forskolin. Retrieval is via the proteosome and/or lysosome. Single channel recordings from H441 cells indicated that phenformin reduced NPo. Treatment of monolayers with 6mM MG132 (proteosomal inhibitor), increased I_amiloride and G_Na+ by ~50%, p<0.05, n=6 and n=3. Subsequent treatment with phenformin decreased the raised amiloridesensitive I_sc and G_Na+ by ~50%, p<0.05, n=6 and n=3. Pretreatment with phenformin prevented the MG132 induced rise in I_amiloride . 100mM chloroquine (lysosomal inhibitor), had no significant effect on I_amiloride (n=7) or G_Na+ (n=3) or the inhibitory effect of phenformin (n=7). 10mM forskolin + 100mM IBMX for 20 minutes induced a ~30% increase in I_amiloride p<0.05, n=8, however, these agents did not increase or restore I_amiloride (n=8) after phenformin treatment. These data indicate that ENaC is recycled via the proteosomal pathway in H441 cells. Activation of AMPK does not decrease Na⁺ transport via increased retrieval of ENaC but inhibits insertion of channels into the apical membrane and Po.