Am J Physiol Cell Physiol AJP: Gastrointestinal and Liver Physiology
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Am J Physiol Cell Physiol (May 28, 2008). doi:10.1152/ajpcell.00369.2007
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Submitted on August 16, 2007
Accepted on May 21, 2008

Small Mouse Cholangiocytes Proliferate in Response to H1 Histamine Receptor Stimulation by Activation of the IP3/CAMK I/CREB Pathway

Heather Francis1, Shannon Glaser2, Sharon DeMorrow3, Eugenio Gaudio4, Yoshiyuki Ueno5, Julie Venter6, David E. Dostal7, Paolo Onori8, Antonio Franchitto4, Marco Marzioni9, Shelley Vaculin10, Bradley Vaculin6, Khurshed Katki11, Monique Stutes12, Jennifer Savage13, and Gianfranco Alpini14*

1 Div. R&E, Scott & White Hospital, Temple, Texas, United States; Div. R&E and Systems Biology and Translational Medicine, Scott & White and Texas A&M Health Science Center, Temple, Texas, United States
2 Div R&E and Medicine, Scott & White and Texas A&M Health Science Center, Temple, Texas, United States
3 Div R&E and Medicine, Scott & White and Texas A&M Health Science Center, Temple, Texas, United States; Temple, Texas, United States
4 Human Anatomy, University of Rome, La Sapienza, Rome, Italy
5 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
6 Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, United States
7 Internal Medicine/Div of Molecular Cardiology, Texas A & M University System-HSC, Temple,, Texas, United States
8 Department of Experimental Medicine, State University of l'Aquila, l'Aquila, Abruzzo, Italy
9 United States; , United States
10 Research, Central Texas Veterans Health Care System, Scott & White and The Texas A&M Health Science Center College of Medicine, Temple, Texas, United States
11 Medicine, Scott & White and Texas A&M Health Science Center, Temple,, Texas, United States
12 Texas A&M Health Science Center, College of Medicine, United States; Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas, United States
13 Medicine, Texas A&M Health Science Center, College of Medicine, Texas, United States
14 Medicine, Central Texas Veterans Health Care System, Scott & White and The Texas A&M Health Science Center College of Medicine, Temple, Texas, United States

* To whom correspondence should be addressed. E-mail: galpini{at}tamu.edu.

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 IP3/Ca2+-dependent signaling pathways, however, data supporting this speculation are lacking. Four histamine receptors exist, HRH1, HRH2, HRH3 and HRH4. In several cells: (i) activation of HRH1 increases [Ca2+]i levels; and (ii) increased [Ca2+]i levels are coupled with calmodulin-dependent stimulation of CaMK and activation of CREB. Hypothesis: 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 HTMT dimaleate (HRH1 agonist) for 24-48 hours 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, 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.




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