1. Signal transduction and hepatocellular bile acid transport: Cross talk between bile acids and second messengers 
Bernard Bouscarel, Spencer D. Kroll, Hans Fromm 
Gastroenterology 
Volume 117, Issue 2, Pages (August 1999)
DOI: /gast

2. 1
Fig. 1. Schematic outlining the mechanism of regulation of cAMP synthesis and calcium mobilization by hormones and bile acids. Increased synthesis of cAMP from ATP and activation of the cAMP-dependent PKA by glucagon (GLUC) occurs after binding of the hormone to the glucagon receptor (R1). This is mediated by the trimeric stimulatory GTP-binding protein (Gs; composed of αs, β, and γ subunits) and activation of adenylyl cyclase (C). In a parallel mechanism, the binding of hormones, such as angiotensin II (ANG), to their respective receptor (R2) inhibits glucagon-induced cAMP synthesis. This is mediated by a trimeric inhibitory GTP-binding protein (composed of αi, β, and γ subunits), either directly through inhibition of the adenylyl cyclase or indirectly through the binding of αi to the β and γ subunits of Gs. Once the hormonal stimulation stops, cytosolic cAMP level returns to basal value because of the presence of phosphodiesterases (PDE) that hydrolyze cAMP to 5'-adenosine monophosphate (5'-AMP). The binding of calcium-mobilizing hormones, such as vasopressin (AVP), to their specific receptor (R3) and mediated by a specific trimeric GTP-binding protein (Gq/11) will activate phospholipase C (PLCβ) and the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to IP3, which will release calcium mainly from the endoplasmic reticulum (ER), and DAG, which will activate PKC. Bile acid (BA) stimulates the release of calcium from the ER through an IP3-independent mechanism as well as calcium influx. Both the phorbol ester PMA and BA stimulate PKC and the inhibition of glucagon-induced cAMP synthesis by uncoupling the glucagon receptor and Gs.
Gastroenterology  , DOI: ( /gast )

3. 2
Fig. 2. Schematic outlining the mechanism of regulation of hepatocellular bile acid influx and efflux by signal-transduction mechanisms. An increase in intracellular calcium, either directly or indirectly through PKC activation, inhibits sinusoidal uptake while stimulating canalicular efflux of bile acids. cAMP, through activation of the cAMP-dependent protein kinase, stimulates sodium-dependent bile acid uptake and canalicular bile acid efflux. BA, bile acid; ADP, adenosine disphosphate; ER, endoplasmic reticulum; N, nucleus; M, mitochondrion.
Gastroenterology  , DOI: ( /gast )

4. 3
Fig. 3. Schematic outlining the mechanism of regulation of hepatocellular signal transduction by bile acids. Bile acids can stimulate either calcium influx from the extracellular domain or calcium release from intracellular organelles (mainly the endoplasmic reticulum), or both, which in turn can activate the calcium/calmodulin-dependent protein kinase. Bile acids can stimulate the translocation and consequently the activation of certain PKC isoforms. Bile acids can inhibit agonist-induced cAMP synthesis. BA, bile acid; Ca2+/CAM PK, calcium and calmodulin protein kinase; ER, endoplasmic reticulum; N, nucleus; M, mitochondrion.
Gastroenterology  , DOI: ( /gast )