Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway
- 1 August 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 295 (2), C499-C513
- https://doi.org/10.1152/ajpcell.00369.2007
Abstract
Cholangiopathies are characterized by the heterogeneous proliferation of different-sized cholangiocytes. Large cholangiocytes proliferate by a cAMP-dependent mechanism. The function of small cholangiocytes may depend on the activation of inositol trisphosphate (IP3)/Ca2+-dependent signaling pathways; however, data supporting this speculation are lacking. Four histamine receptors exist (HRH1, HRH2, HRH3, and HRH4). In several cells: 1) activation of HRH1 increases intracellular Ca2+concentration levels; and 2) increased [Ca2+]ilevels are coupled with calmodulin-dependent stimulation of calmodulin-dependent protein kinase (CaMK) and activation of cAMP-response element binding protein (CREB). HRH1 agonists modulate small cholangiocyte proliferation by activation of IP3/Ca2+-dependent CaMK/CREB. We evaluated HRH1 expression in cholangiocytes. Small and large cholangiocytes were stimulated with histamine trifluoromethyl toluidide (HTMT dimaleate; HRH1 agonist) for 24–48 h with/without terfenadine, BAPTA/AM, or W7 before measuring proliferation. Expression of CaMK I, II, and IV was evaluated in small and large cholangiocytes. We measured IP3, Ca2+and cAMP levels, phosphorylation of CaMK I, and activation of CREB (in the absence/presence of W7) in small cholangiocytes treated with HTMT dimaleate. CaMK I knockdown was performed in small cholangiocytes stimulated with HTMT dimaleate before measurement of proliferation and CREB activity. Small and large cholangiocytes express HRH1, CaMK I, and CaMK II. Small (but not large) cholangiocytes proliferate in response to HTMT dimaleate and are blocked by terfenadine (HRH1 antagonist), BAPTA/AM, and W7. In small cholangiocytes, HTMT dimaleate increased IP3/Ca2+levels, CaMK I phosphorylation, and CREB activity. Gene knockdown of CaMK I ablated the effects of HTMT dimaleate on small cholangiocyte proliferation and CREB activation. The IP3/Ca2+/CaMK I/CREB pathway is important in the regulation of small cholangiocyte function.Keywords
This publication has 65 references indexed in Scilit:
- Prolactin stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2+-dependent PKC isoformsBMC Physiology, 2007
- H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathwayLaboratory Investigation, 2007
- Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP3/Ca2+-dependent downregulation of SRC/ERK1/2American Journal of Physiology-Cell Physiology, 2007
- cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathwayJournal of Hepatology, 2004
- Functional Screening of G Protein–Coupled Receptors by Measuring Intracellular Calcium with a Fluorescence Microplate ReaderSLAS Discovery, 2002
- Isolation and comparison of rat cDNAs encoding Ca2+/calmodulin-dependent protein kinase I isoformsBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1997
- A morphometric study of the epithelium lining the rat intrahepatic biliary treeJournal of Hepatology, 1996
- A Novel Highly Specific and Potent Inhibitor of Calmodulin-Dependent Protein Kinase IIBiochemical and Biophysical Research Communications, 1995
- ATP-Activated Chloride Permeability in Biliary Epithelial Cells Is Regulated by Calmodulin-Dependent Protein Kinase IIBiochemical and Biophysical Research Communications, 1995
- Stabilization of Calmodulin-dependent Protein Kinase II through the Autoinhibitory DomainOnline Journal of Public Health Informatics, 1995