Zusammenfassung
Previous in vitro studies suggested that Cl- currents produced by the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7) are inhibited by the alpha 1 isoform of the adenosine monophosphate (AMP)-stimulated kinase (AMPK). AMPK is a serine/threonine kinase that is activated during metabolic stress. It has been proposed as a potential mediator for transport-metabolism coupling in ...
Zusammenfassung
Previous in vitro studies suggested that Cl- currents produced by the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7) are inhibited by the alpha 1 isoform of the adenosine monophosphate (AMP)-stimulated kinase (AMPK). AMPK is a serine/threonine kinase that is activated during metabolic stress. It has been proposed as a potential mediator for transport-metabolism coupling in epithelial tissues. All previous studies have been performed in vitro and thus little is known about the regulation of Cl- secretion by AMPK in vivo. Using AMPK alpha 1(-/-) mice and wild-type littermates, we demonstrate that phenformin, an activator of AMPK, strongly inhibits cAMP-activated Cl- secretion in mouse airways and colon, when examined in ex vivo in Ussing chamber recordings. However, phenformin was equally effective in AMPK alpha 1(-/-) and wild-type animals, suggesting additional AMPK-independent action of phenformin. Phenformin inhibited CFTR Cl- conductance in basolaterally permeabilized colonic epithelium from AMPK alpha 1(+/+) but not AMPK alpha 1(-/-) mice. The inhibitor of AMPK compound C enhanced CFTR-mediated Cl- secretion in epithelial tissues of AMPK alpha 1(-/-) mice, but not in wild-type littermates. There was no effect on Ca2+-mediated Cl- secretion, activated by adenosine triphosphate or carbachol. Moreover CFTR-dependent Cl- secretion was enhanced in the colon of AMPK alpha 1(-/-) mice, as indicated in Ussing chamber ex vivo and rectal PD measurements in vivo. Taken together, these data suggest that epithelial Cl- secretion mediated by CFTR is controlled by AMPK in vivo.
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