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Articles in PresS, published online ahead of print August 1, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00041.2002
Submitted on January 28, 2002
Accepted on July 24, 2002
1 Department of Physiology, Tufts University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: irwin.arias{at}tufts.edu.
Bile secretion is a dynamic process mediated by ATP-binding cassette (ABC) transporters which couple ATP hydrolysis to the excretory transport of specific substrates. Our previous studies performed in rat bile canalicular membrane vesicles and WIF-B9 cells, a polarized rat hepatoma-human fibroblast hybrid cell line, revealed that cAMP-induced trafficking of ABC transporters to the canalicular membrane and their subsequent activation require phosphoinositide 3-kinase (PI 3-K) lipid products. In the present studies canalicular secretion of fluorescein isothiocyanate-glycocholate in WIF-B9 cells significantly increased following addition of cAMP and a decapeptide which enhances PI 3-K activity; these effects were inhibited by preincubation with wortmannin (100 nM). These functional studies indicate that cAMP acts through a wortmannin-inhibitable mechanism(s) to enhance canalicular bile acid secretion. To determine the mechanism(s) whereby cAMP activates PI 3-K, we examined signal transduction pathways in WIF-B9 and, as a control, COS-7 cells. cAMP activated PI 3-K in both cell lines in a time- and dose-dependent, and phosphotyrosine-independent manner. PI 3-K activity increased in association with p110
in both cell lines. Activation of p110ß was detected only in COS-7 cells; p110ß was not expressed in WIF-B9 cells. The effect of cAMP on PI 3-K was KT5720-sensitive, suggesting the involvement of protein kinase A. Expression of a dominant-negative construct of ß-adrenergic receptor kinase C-terminus (ßARKct), which blocks Gß
signaling, decreased PI 3-K activation to less than 30% in both cell lines. In addition, cAMP induced an increase in GTP-bound Ras in COS-7 cells which was unaffected by wortmannin. Expression of dominant negative Ras abolished cAMP-mediated PI 3-K activation and expression of ßARKct attenuated Ras activation which suggests that cAMP-induced activation of PI 3-K is downstream of Ras and Gß in COS-7 cells. In contrast, cAMP did not induce Ras activation in WIF-B9 cells. These data indicate that cAMP activates PI 3-K in a cell type-specific manner, and provide insight regarding mechanisms of PI 3-K activation which is required for bile acid secretion in liver and WIF-B9 cells.
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