Large cholangiocytes secrete
bicarbonate in response to
secretin and proliferate after bile duct
ligation by activation of cyclic
adenosine 3', 5'-monophosphate signaling. The Ca(2+)-dependent
adenylyl cyclase 8 (AC8, expressed by large cholangiocytes) regulates
secretin-induced choleresis. Ca(2+)-dependent
protein kinase C (PKC) regulates small cholangiocyte function. Because
gamma-aminobutyric acid (
GABA) affects cell functions by activation of both Ca(2+) signaling and inhibition of AC, we sought to develop an in vivo model characterized by large cholangiocyte damage and proliferation of small ducts. Bile duct
ligation rats were treated with
GABA for one week, and we evaluated:
GABA(A),
GABA(B), and
GABA(C) receptor expression; intrahepatic bile duct mass (IBDM) and the percentage of apoptotic cholangiocytes;
secretin-stimulated choleresis; and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation and activation of Ca(2+-)dependent PKC
isoforms and AC8 expression. We found that both small and large cholangiocytes expressed
GABA receptors.
GABA: (i) induced apoptosis of large cholangiocytes and reduced large IBDM; (ii) decreased
secretin-stimulated choleresis; and (iii) reduced ERK1/2 phosphorylation and AC8 expression in large cholangiocytes. Small cholangiocytes: (i) proliferated leading to increased IBDM; (ii) displayed activation of PKCbetaII; and (iii) de novo expressed
secretin receptor,
cystic fibrosis transmembrane regulator, Cl(-)/HCO(3)(-)
anion exchanger 2 and AC8, and responded to
secretin. Therefore, in pathologies of large ducts, small ducts replenish the biliary epithelium by amplification of Ca(2+)-dependent signaling and acquisition of large cholangiocyte phenotypes.