Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-gamma expression and decrease of PKA activity.
To determine the role and mechanisms of action by which dopaminergic innervation modulates ductal secretion in bile duct-ligated rats, we determined the expression of D1, D2, and D3 dopaminergic receptors in cholangiocytes. We evaluated whether D1, D2 (quinelorane), or D3 dopaminergic receptor agonists influence basal and secretin-stimulated choleresis and lumen expansion in intrahepatic bile duct units (IBDU) and cAMP levels in cholangiocytes in the absence or presence of BAPTA-AM, chelerythrine, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine (H7), or rottlerin. We evaluated whether 1) quinelorane effects on ductal secretion were associated with increased expression of Ca(2+)-dependent PKC isoforms and 2) increased expression of PKC causes inhibition of PKA activity. Quinelorane inhibited secretin-stimulated choleresis in vivo and IBDU lumen space, cAMP levels, and PKA activity in cholangiocytes. The inhibitory effects of quinelorane on secretin-stimulated ductal secretion and PKA activity were blocked by BAPTA-AM, chelerythrine, and H7. Quinelorane effects on ductal secretion were associated with activation of the Ca(2+)-dependent PKC-gamma but not other PKC isoforms. The dopaminergic nervous system counterregulates secretin-stimulated ductal secretion in experimental cholestasis.
Glaser
Shannon
S
Department of Internal Medicine, Texas A&M University System Health Sciences Center, College of Medicine, Temple, Texas 76504, USA.
Alvaro
Domenico
D
Roskams
Tania
T
Phinizy
Jo Lynne
JL
Stoica
George
G
Francis
Heather
H
Ueno
Yoshiyuki
Y
Barbaro
Barbara
B
Marzioni
Marco
M
Mauldin
Jeremy
J
Rashid
Sobia
S
Mancino
Maria Grazia
MG
LeSage
Gene
G
Alpini
Gianfranco
G
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism; D001646:Bile / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012633:Secretin / Q000378:metabolism*
D000098:Acetophenones; D000470:Alkaloids; D053119:Benzophenanthridines; D001578:Benzopyrans; D001639:Bicarbonates; D002614:Chelating Agents; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D010617:Phenanthridines; D011804:Quinolines; D017448:Receptors, Dopamine D2; D012633:Secretin; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP; C085746:rottlerin; C016299:chelerythrine; C087857:protein kinase C gamma; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D004298:Dopamine; C047726:quinelorane