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Am J Physiol Cell Physiol 284: C1297-C1308, 2003. First published January 2, 2003; doi:10.1152/ajpcell.00227.2002
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Vol. 284, Issue 5, C1297-C1308, May 2003

Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells

Kenneth R. Hallows1,2, Gary P. Kobinger2,3, James M. Wilson2,3, Lee A. Witters4, and J. Kevin Foskett5

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-beta -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 alpha -toxin also inhibited CFTR, an effect that was unrelated to adenosine receptors. Finally, overexpression of a kinase-dead mutant AMPK-alpha 1 subunit (alpha 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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