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1 Renal-Electrolyte Division, Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
2 Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; The Wistar Institute, Philadelphia, PA, USA
3 Medicine and Biochemistry, Dartmouth Medicial School, Hanover, NH, USA
4 Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: foskett{at}mail.med.upenn.edu.
CFTR is a cAMP-activated, ATP-gated Cl- channel and cellular conductance regulator, but the detailed mechanisms of CFTR regulation and its regulation of other transport proteins remain obscure. We previously identified the metabolic sensor AMP-activated protein kinase (AMPK) as a novel interacting protein with CFTR and found that AMPK phosphorylated CFTR and inhibited CFTR-dependent whole-cell conductances when co-expressed with CFTR in Xenopus oocytes. To address the physiological relevance of the CFTR-AMPK interaction, we have now studied polarized epithelia and have evaluated the localization of endogenous AMPK and CFTR and measured CFTR activity with modulation of AMPK activity. By immunofluorescent imaging, AMPK and CFTR share an overlapping apical distribution in several rat epithelial tissues, including nasopharynx, submandibular gland, pancreas, and ileum. CFTR-dependent short-circuit currents (Isc) were measured in polarized T84 cells grown on permeable supports, and several independent methods were used to modulate endogenous AMPK activity. Activation of endogenous AMPK with the cell-permeant adenosine analogue AICAR inhibited forskolin-stimulated CFTR-dependent Isc in both non-permeabilized monolayers and in monolayers with nystatin-permeabilization of the basolateral membrane. Raising intracellular [AMP] in monolayers with basolateral membranes permeabilized with 
-toxin also inhibited CFTR, an effect that was unrelated to adenosine receptors. Finally, over-expression of a kinase-dead mutant AMPK-1 subunit (1-K45R) enhanced forskolin-stimulated Isc in polarized T84 monolayers, consistent with a dominant-negative reduction in the inhibition of CFTR by endogenous AMPK. These results indicate that AMPK plays a physiological role in modulating CFTR activity in polarized epithelia and suggest a novel paradigm for the coupling of ion transport to cellular metabolism.
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