Insulin inhibits secretin-induced ductal secretion by activation of PKC alpha and inhibition of PKA activity

LeSage, Gene; Marucci, Luca; Alvaro, Domenico; Glaser, Shannon; Benedetti, Antonio; Marzioni, Marco; Patel, Tushar; Francis, Heather; Phinizy, Jo Lynne; Alpini, Gianfranco

doi:10.1053/jhep.2002.35537

Cited by 48 publications

(72 citation statements)

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“…Insulin and ursodeoxycholate inhibition of secretin-stimulated choleresis is associated with activation of PKC-␣. 21,42 D2 dopaminergic receptor agonists inhibit secretinstimulated ductal secretion via activation of PKC-␥. 11 The differential cross-talk between [Ca 2ϩ ] i and adenylyl cyclase (which leads to stimulatory or inhibitory effects on secretin-stimulated cAMP levels and ductal secretion) 7,9,11,21,22,42 depends on the type of receptor (M3 acetylcholine, 9 D2 dopaminergic, 11 insulin, 21 or gastrin 7 ) or transporter (apical bile acid transporter 22,42,43 ) that is up-or downregulated.…”

Section: Discussionmentioning

confidence: 99%

“…5,20 Cell viability (Ϸ97%) was determined via trypan blue exclusion. Large secretin-responsive IBDUs (size range of 50-100 m with a mean diameter of 70 m) 21 from BDL rats were isolated as described by the authors. 21 Expression of ␣-1A/1C -1B, and ␤-1 Adrenergic Receptors…”

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

“…We evaluated the effects of phenylephrine on basal and secretin-stimulated fluid secretion in large IBDUs from BDL rats. 21 Ductal secretion was evaluated from the changes in the area of IBDU lumen space, as described by the authors, 18 after basolateral perfusion with: (1) 0.2% BSA (basal) for 10 minutes; (2) secretin (100 nmol/L) with 0.2% BSA for 10 minutes; or (3) phenylephrine or dobutamine (10 mol/L) for 10 minutes in the absence or presence of secretin (100 nmol/L) with 0.2% BSA for 10 minutes. Because phenylephrine increased the stimulatory effect of secretin on IBDU lumen space, we evaluated the effect of benoxathian (10 mol/L); BAPTA/AM (50 mol/L), an intracellular Ca 2ϩ chelator 7,9 ); and Gö6976 (1 mol/L), a Ca 2ϩ -dependent PKC-␣ inhibitor, 26 in the presence of phenylephrine (10 mol/L) ϩ secretin (100 nmol/L) with 0.2% BSA.…”

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

“…Cholangiocyte cAMP levels were measured via Radioimmunoassay. 4,5,7,21 Are Phenylephrine Effects on Secretin-stimulated Ductal Secretion of BDL Rats Associated With Changes in IP 3 /Ca 2؉ Levels and Activation of PKC Isoforms?…”

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

“…3 PKA assay was performed using a PepTag Assay Protein Kinase Kit (Promega, Madison, WI) for PKA according to the manufacturer's instructions. 21 Cholangiocytes (5 ϫ 10 6 ) from BDL rats were stimulated at 37°C with: (1) 0.2% BSA for 30 minutes; (2) …”

Section: Is Phenylephrine-induced Increase In Pkc-␣ or Pkc-␤-ii Assocmentioning

confidence: 99%

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α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

et al. 2004

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Acetylcholine potentiates secretin-stimulated ductal secretion by Ca 2؉ -calcineurin-mediated modulation of adenylyl cyclase. D2 dopaminergic receptor agonists inhibit secretin-stimulated ductal secretion via activation of protein kinase C (PKC)-␥. No information exists regarding the effect of adrenergic receptor agonists on ductal secretion in a model of cholestasis induced by bile duct ligation (BDL). We evaluated the expression of ␣-1A/1C, -1␤ and ␤-1 adrenergic receptors in liver sections and cholangiocytes from normal and BDL rats. We evaluated the effects of the ␣-1 and ␤-1 adrenergic receptor agonists (phenylephrine and dobutamine, respectively) on bile and bicarbonate secretion and cholangiocyte IP 3 and Ca 2؉ levels in normal and BDL rats. We measured the effect of phenylephrine on lumen expansion in intrahepatic bile duct units (IBDUs) and cyclic adenosine monophosphate (cAMP) levels in cholangiocytes from BDL rats in the absence or presence of BAPTA/AM and Gö6976 (a PKC-␣ inhibitor). We evaluated if the effects of phenylephrine on ductal secretion were associated with translocation of PKC isoforms leading to increased protein kinase A activity. ␣-1 and ␤-1 adrenergic receptors were present mostly in the basolateral domain of cholangiocytes and, following BDL, their expression increased. Phenylephrine, but not dobutamine, increased secretin-stimulated choleresis in BDL rats. Phenylephrine did not alter basal but increased secretin-stimulated IBDU lumen expansion and cAMP levels, which were blocked by BAPTA/AM and Gö6976. S ecretin stimulates ductal HCO 3Ϫ secretion 1-5 by interacting with receptors expressed only by rat cholangiocytes. 6 This interaction induces an increase in intracellular cyclic adenosine 3Ј,5Ј-monophosphate (cAMP) levels, 4,5,7 which leads to the opening of cystic fibrosis transmembrane conductance regulator channels, 8 followed by activation of the apically located Cl Ϫ /HCO 3 Ϫ exchanger 9 with secretion of HCO 3 Ϫ into bile. 1 Acetylcholine increases intracellular Ca 2ϩ ([Ca 2ϩ ] i ) levels and oscillations in rat cholangiocytes due to influx of extracellular Ca 2ϩ and mobilization of thapsigarginsensitive [Ca 2ϩ ] i stores. 10 It also increases secretin-stimulated ductal HCO 3 Ϫ secretion via Ca 2ϩ -calcineurin mediated modulation of adenylyl cyclase. 9 The D2 dopaminergic receptor agonist quinelorane inhibits secretinstimulated ductal secretion via activation of the Ca 2ϩ -dependent protein kinase C (PKC)-␥. 11 Adrenergic nerve stimulation causes a decrease in bile flow in the isolated perfused rat liver via interaction with ␣-1 adrenergic receptors. 12 In isolated perfused rat liver, adrenaline induces

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Section: Discussionmentioning

confidence: 99%

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

Section: Is Phenylephrine-induced Increase In Pkc-␣ or Pkc-␤-ii Assocmentioning

confidence: 99%

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α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

et al. 2004

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Biliary Epithelial Cells

Dufour¹

2007

Textbook of Hepatology

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Functional Anatomy of Normal Bile Ducts

Strazzabosco

Fabris

2008

The Anatomical Record

114

104

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The biliary tree is a complex network of conduits that begins with the canals of Hering and progressively merges into a system of interlobular, septal, and major ducts which then coalesce to form the extrahepatic bile ducts, which finally deliver bile to the gallbladder and to the intestine. The biliary epithelium shows a morphological heterogeneity that is strictly associated with a variety of functions performed at the different levels of the biliary tree. In addition to funneling bile into the intestine, cholangiocytes (the epithelial cells lining the bile ducts) are actively involved in bile production by performing both absorbitive and secretory functions. More recently, other important biological properties restricted to cholangiocytes lining the smaller bile ducts have been outlined, with regard to their plasticity (i.e., the ability to undergo limited phenotypic changes), reactivity (i.e., the ability to participate in the inflammatory reaction to liver damage), and ability to behave as liver progenitor cells. Functional interactions with other branching systems, such as nerve and vascular structures, are crucial in the modulation of the different cholangiocyte functions.

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Insulin inhibits secretin-induced ductal secretion by activation of PKC alpha and inhibition of PKA activity

Cited by 48 publications

References 50 publications

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

Biliary Epithelial Cells

Functional Anatomy of Normal Bile Ducts

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