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Differential Regulation of Cholangiocyte Growth by Activation of Different Histamine Receptor Subtypes
Author(s) -
Francis Heather,
Venter Julie,
De Morrow Sharon,
Glaser Shan,
Vaculin Bradley,
Vaculin Shelley,
Ueno Yoshiyuki,
Alpini Gianfranco
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1324
Subject(s) - cholangiocyte , histamine , endocrinology , medicine , chemistry , phosphorylation , receptor , histamine h1 receptor , biology , microbiology and biotechnology , biochemistry , antagonist
Histamine exerts its functions by binding to four histamine G‐coupled receptor proteins (H1R, H2R, H3R and H4R). Cross‐talk between Ca 2+ and cAMP regulates cholangiocyte growth. We tested the HYPOTHESIS that the activation of H3/H4R decreases cholangiocyte proliferation, whereas activation of H1/H2R increases biliary growth. The expression of H1‐H4R was evaluated in cholangiocytes from normal and bile duct ligated (BDL) rats. BDL (immediately after BDL) rats were treated daily with RAMH (a H3/H4R agonist, 10 mg/Kg BW) for one week. Normal rats were treated with the selective histamine agonists: H1R, HTMT dimaleate (375 μg/day) or H2R, amthamine dihydrobromide (375 μg/day) for 1 week. Following in vitro treatment of: BDL cholangiocytes with RAMH (10 μM); and normal cholangiocytes with H1/H2R agonists we evaluated cholangiocyte proliferation and transduction pathways.Results: Cholangiocytes express H1‐H4R. RAMH inhibition of BDL cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk‐1 phosphorylation. H1/H2‐induced increase in cholangiocyte growth was associated with Ca 2+ ‐(H1R) or cAMP‐(H2R) dependent phosphorylation of Src/ERK1/2. Conclusion: We propose that a balance between the stimulatory (by activation of H1/H2R) and inhibitory (by activation of H3/H4R) effects of histamine regulates cholangiocyte growth in liver diseases.