Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile

Noritaka Minagawa, Jun Nagata, Kazunori Shibao, Anatoliy I. Masyuk, Dawidson A. Gomes, Michele A. Rodrigues, Gene Lesage, Yasutada Akiba, Jonathan D. Kaunitz, Barbara E. Ehrlich, Nicholas F La Russo, Michael H. Nathanson

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Bicarbonate secretion is a primary function of cholangiocytes. Either adenosine 3′,5′-cyclic monophosphate (cAMP) or cytosolic Ca2+ can mediate bicarbonate secretion, but these are thought to act through separate pathways. We examined the role of the inositol 1,4,5-trisphosphate receptor (InsP3R) in mediating bicarbonate secretion because this is the only intracellular Ca2+ release channel in cholangiocytes. Methods: Intrahepatic bile duct units (IBDUs) were microdissected from rat liver then luminal pH was examined by confocal microscopy during IBDU microperfusion. Cyclic AMP was increased using forskolin or secretin, and Ca2+ was increased using acetylcholine (ACh) or adenosine triphosphate (ATP). Apyrase was used to hydrolyze extracellular ATP, and suramin was used to block apical P2Y ATP receptors. In selected experiments, IBDUs were pretreated with short interfering RNA (siRNA) to silence expression of specific InsP3R isoforms. Results: Both cAMP and Ca2+ agonists increased luminal pH. The effect of ACh on luminal pH was reduced by siRNA for basolateral (types I and II) but not apical (type III) InsP3R isoforms. The effect of forskolin on luminal pH was reduced by a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor and by siRNA for the type III InsP3R. Luminal apyrase or suramin blocked the effects of forskolin but not ACh on luminal pH. Conclusions: Cyclic AMP-induced ductular bicarbonate secretion depends on an autocrine signaling pathway that involves CFTR, apical release of ATP, stimulation of apical nucleotide receptors, and then activation of apical, type III InsP3Rs. The primary role of CFTR in bile duct secretion may be to regulate secretion of ATP rather than to secrete chloride and/or bicarbonate.

Original languageEnglish (US)
Pages (from-to)1592-1602
Number of pages11
JournalGastroenterology
Volume133
Issue number5
DOIs
StatePublished - Nov 2007

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Bicarbonates
Bile
Cyclic AMP
Intrahepatic Bile Ducts
Adenosine Triphosphate
Cystic Fibrosis Transmembrane Conductance Regulator
Colforsin
Apyrase
Small Interfering RNA
Acetylcholine
Suramin
Protein Isoforms
Autocrine Communication
Inositol 1,4,5-Trisphosphate Receptors
Purinergic P1 Receptors
Secretin
Bile Ducts
Confocal Microscopy
Adenosine
Chlorides

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Minagawa, N., Nagata, J., Shibao, K., Masyuk, A. I., Gomes, D. A., Rodrigues, M. A., ... Nathanson, M. H. (2007). Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile. Gastroenterology, 133(5), 1592-1602. https://doi.org/10.1053/j.gastro.2007.08.020

Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile. / Minagawa, Noritaka; Nagata, Jun; Shibao, Kazunori; Masyuk, Anatoliy I.; Gomes, Dawidson A.; Rodrigues, Michele A.; Lesage, Gene; Akiba, Yasutada; Kaunitz, Jonathan D.; Ehrlich, Barbara E.; La Russo, Nicholas F; Nathanson, Michael H.

In: Gastroenterology, Vol. 133, No. 5, 11.2007, p. 1592-1602.

Research output: Contribution to journalArticle

Minagawa, N, Nagata, J, Shibao, K, Masyuk, AI, Gomes, DA, Rodrigues, MA, Lesage, G, Akiba, Y, Kaunitz, JD, Ehrlich, BE, La Russo, NF & Nathanson, MH 2007, 'Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile', Gastroenterology, vol. 133, no. 5, pp. 1592-1602. https://doi.org/10.1053/j.gastro.2007.08.020
Minagawa N, Nagata J, Shibao K, Masyuk AI, Gomes DA, Rodrigues MA et al. Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile. Gastroenterology. 2007 Nov;133(5):1592-1602. https://doi.org/10.1053/j.gastro.2007.08.020
Minagawa, Noritaka ; Nagata, Jun ; Shibao, Kazunori ; Masyuk, Anatoliy I. ; Gomes, Dawidson A. ; Rodrigues, Michele A. ; Lesage, Gene ; Akiba, Yasutada ; Kaunitz, Jonathan D. ; Ehrlich, Barbara E. ; La Russo, Nicholas F ; Nathanson, Michael H. / Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile. In: Gastroenterology. 2007 ; Vol. 133, No. 5. pp. 1592-1602.
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AU - Minagawa, Noritaka

AU - Nagata, Jun

AU - Shibao, Kazunori

AU - Masyuk, Anatoliy I.

AU - Gomes, Dawidson A.

AU - Rodrigues, Michele A.

AU - Lesage, Gene

AU - Akiba, Yasutada

AU - Kaunitz, Jonathan D.

AU - Ehrlich, Barbara E.

AU - La Russo, Nicholas F

AU - Nathanson, Michael H.

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