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Cited by 54Adenosine and Purinergic SignalingDrug Transport and Resistance MechanismsIon Transport and Channel Regulation

Adenosine Triphosphate Release and Purinergic (P2) Receptor–Mediated Secretion in Small and Large Mouse Cholangiocytes

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Woo, Kangmee, Sathe, Meghana, Kresge, Charles, Esser, Victoria, Ueno, Yoshiyuki, Venter, Julie, Glaser, Shannon S., Alpini, Gianfranco +1 more·2010·Hepatology
DOI 10.1002/hep.23883PMC PMC2967625
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Abstract

Adenosine triphosphate (ATP) is released from cholangiocytes into bile and is a potent secretogogue by increasing intracellular Ca2+ and stimulating fluid and electrolyte secretion via binding purinergic (P2) receptors on the apical membrane. Although morphological differences exist between small and large cholangiocytes (lining small and large bile ducts, respectively), the role of P2 signaling has not been previously evaluated along the intrahepatic biliary epithelium. The aim of these studies therefore was to characterize ATP release and P2-signaling pathways in small (MSC) and large (MLC) mouse cholangiocytes. The findings reveal that both MSCs and MLCs express P2 receptors, including P2X4 and P2Y2. Exposure to extracellular nucleotides (ATP, uridine triphosphate, or 2′,3′-O-[4-benzoyl-benzoyl]-ATP) caused a rapid increase in intracellular Ca2+ concentration and in transepithelial secretion ( I sc) in both cell types, which was inhibited by the Cl− channel blockers 5-nitro-2-(-3-phenylpropylamino)-benzoic acid (NPPB) or niflumic acid. In response to mechanical stimulation (flow/shear or cell swelling secondary to hypotonic exposure), both MSCs and MLCs exhibited a significant increase in the rate of exocytosis, which was paralleled by an increase in ATP release. Mechanosensitive ATP release was two-fold greater in MSCs compared to MLCs. ATP release was significantly inhibited by disruption of vesicular trafficking by monensin in both cell types. Conclusion: These findings suggest the existence of a P2 signaling axis along intrahepatic biliary ducts with the “upstream” MSCs releasing ATP, which can serve as a paracrine signaling molecule to “downstream” MLCs stimulating Ca2+-dependent secretion. Additionally, in MSCs, which do not express the cystic fibrosis transmembrane conductance regulator, Ca2+-activated Cl− efflux in response to extracellular nucleotides represents the first secretory pathway clearly identified in these cholangiocytes derived from the small intrahepatic ducts. (Hepatology 2010)

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  • Secreted ATP acts in an autocrine or paracrine manner through P2X4R receptors to coordinate cholangiocyte responses and regulate bile formation and secretion.

    “The secreted ATP, in turn, acts in an autocrine or paracrine manner through P2X4R receptors to coordinate cholangiocyte responses and regulate bile formation and secretion.127,128”

    From Mechanosensitive calcium ion channels Piezo1: A therapeutic target in liver disease (2025) · cites this paper as [128]

    The Discussion (page unavailable) proposes that ATP released by upstream mouse cholangiocytes signals to downstream cholangiocytes through P2 receptors and contributes to bile formation. The Results identify functional P2X4 receptors, but also P2Y receptors; they do not establish that P2X4 specifically mediates the claimed coordination and secretion. (LLM, conf=0.86)

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Authors
Woo, K., Sathe, M., Kresge, C., Esser, V., Ueno, Y., Venter, J., Glaser, S. S., Alpini, G., & Feranchak, A. P.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Tohoku University (JP)
  • Baylor Scott & White Medical Center - Temple (US)
  • Texas A&M Health Science Center (US)
Corresponding author
Feranchak, Andrew P.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2010-11
Volume
52
Issue
5
Pages
1819-1828
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.23883
PMC
PMC2967625
OpenAlex
W2141469837
Cited by
54
References
0
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 5 · 2017: 2 · 2015: 7 · 2014: 6 · 2013: 8 · 2012: 5
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1765 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078587, DK054811, DK-078587, R01DK054811)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
cholangiocytes, ATP release, purinergic P2 receptors, P2X4, bile secretion, intracellular calcium, chloride secretion, exocytosis, vesicle trafficking, paracrine signaling, cystic fibrosis transmembrane conductance regulator
MeSH terms
Adenosine Triphosphate, Animals, Antigens, Polyomavirus Transforming, Calcium, Exocytosis, Mice, Inbred BALB C, RNA, Transfection, Signal Transduction, Receptors, Purinergic P2, Cystic Fibrosis Transmembrane Conductance Regulator, Reverse Transcriptase Polymerase Chain Reaction, Mice, Receptors, Purinergic P2X

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