title: Regulation of Cl(-) secretion by AMPK in vivo.
abstract: Previous in vitro studies suggested that Cl(-) currents produced by the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7) are inhibited by the alpha1 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 AMPKalpha1(-/-) 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 AMPKalpha1(-/-) and wild-type animals, suggesting additional AMPK-independent action of phenformin. Phenformin inhibited CFTR Cl(-) conductance in basolaterally permeabilized colonic epithelium from AMPKalpha1(+/+) but not AMPKalpha1(-/-) mice. The inhibitor of AMPK compound C enhanced CFTR-mediated Cl(-) secretion in epithelial tissues of AMPKalpha1(-/-) mice, but not in wild-type littermates. There was no effect on Ca(2+)-mediated Cl(-) secretion, activated by adenosine triphosphate or carbachol. Moreover CFTR-dependent Cl(-) secretion was enhanced in the colon of AMPKalpha1(-/-) 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.
authors.affiliation: Department of Physiology, University of Regensburg, Germany.
authors.forename: Patthara
authors.initials: P
authors.lastname: Kongsuphol
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hieke
authors.forename: Jiraporn
authors.initials: J
authors.lastname: Ousingsawat
authors.forename: Joana
authors.initials: J
authors.lastname: Almaca
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann