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1 Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; Departments of 2 Medicine and 5 Physiology, University of Pennsylvania School of Medicine, and 3 Wistar Institute, Philadelphia, Pennsylvania 19104; and 4 Departments of Medicine and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755
The cystic fibrosis transmembrane
conductance regulator (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 protein interacting with CFTR and found that AMPK phosphorylated CFTR and
inhibited CFTR-dependent whole cell conductances when coexpressed 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 analog
5-amino-4-imidazolecarboxamide-1-
-D-ribofuranoside (AICAR) inhibited forskolin-stimulated CFTR-dependent
Isc in nonpermeabilized monolayers and
monolayers with nystatin permeabilization of the basolateral membrane.
Raising intracellular AMP concentration in monolayers with basolateral
membranes permeabilized with 
-toxin also inhibited CFTR, an effect
that was unrelated to adenosine receptors. Finally, overexpression 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.
ion transport; cell metabolism; epithelial transport; chloride channel; cystic fibrosis
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