Mechanisms by which cAMP increases bile acid secretion in rat liver and canalicular membrane vesicles.
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.
Misra
Suniti
S
Dept. of Physiology, Tufts Univ. School of Medicine, 136 Harrison Ave., M&V7, Boston, MA 02111, USA.
Varticovski
Lyuba
L
Arias
Irwin M
IM
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D003078:Colchicine / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000378:metabolism / Q000494:pharmacology; D000077191:Wortmannin
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000730:Androstadienes; D001647:Bile Acids and Salts; D003994:Bucladesine; D002352:Carrier Proteins; D003078:Colchicine; D000242:Cyclic AMP; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013656:Taurocholic Acid; D000077191:Wortmannin; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat