Affiliation:
1. Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111
Abstract
Bile acid secretion induced by cAMP and taurocholate is associated with recruitment of several ATP binding cassette (ABC) transporters to the canalicular membrane. Taurocholate-mediated bile acid secretion and recruitment of ABC transporters are phosphatidylinositol 3-kinase (PI3K) dependent and require an intact microtubular apparatus. We examined mechanisms involved in cAMP-mediated bile acid secretion. Bile acid secretion induced by perfusion of rat liver with dibutyryl cAMP was blocked by colchicine and wortmannin, a PI3K inhibitor. Canalicular membrane vesicles isolated from cAMP-treated rats manifested increased ATP-dependent transport of taurocholate and PI3K activity that were reduced by prior in vivo administration of colchicine or wortmannin. Addition of a PI3K lipid product, phosphoinositide 3,4-bisphosphate, but not its isomer, phosphoinositide 4,5-bisphosphate, restored ATP-dependent taurocholate in these vesicles. Addition of a decapeptide that activates PI3K to canalicular membrane vesicles increased ATP-dependent transport above baseline activity. In contrast to effects induced by taurocholate, cAMP-stimulated intracellular trafficking of the canalicular ABC transporters was unaffected by wortmannin, and recruitment of multidrug resistance protein 2, but not bile salt excretory protein (bsep), was partially decreased by colchicine. These studies indicate that trafficking of bsep and other canalicular ABC transporters to the canalicular membrane in response to cAMP is independent of PI3K activity. In addition, PI3K lipid products are required for activation of bsep in the canalicular membrane. These observations prompt revision of current concepts regarding the role of cAMP and PI3K in intracellular trafficking, regulation of canalicular bsep, and bile acid secretion.
Publisher
American Physiological Society
Subject
Physiology (medical),Gastroenterology,Hepatology,Physiology
Reference50 articles.
1. A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells
2. The effect of dibutyryl cyclic AMP on the excretion of taurocholic acid from isolated rat liver cells
3. The Phosphoinositide 3-Kinase Pathway
4. Carey MC and Duane WC. Enterohepatic circulation. In: The Liver: Biology and Pathobiology, edited by Arias IM, Boyer JL, Fausto N, Jacoby WV, Schachter DA, and Shafritz DA. New York: Raven, 1994, p. 69–78.
5. Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, and Cantley LC. Purification and characterization of phosphoinositide 3-kinase from rat liver. J Biol Chem 265: 19704–19711, 1990.
Cited by
51 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献