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

Woo, Kangmee; Sathe, Meghana; Kresge, Charles; Esser, Victoria; Ueno, Yoshiyuki; Venter, Julie; Glaser, Shannon; Alpini, Gianfranco; Feranchak, Andrew P.

doi:10.1002/hep.23883

Cited by 43 publications

(47 citation statements)

References 28 publications

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“…Each model system expresses phenotypic features of differentiated biliary epithelium, including receptors, signaling pathways, and ion channels, similar to those found in primary cells (7,29,30). Unlike Mz-Cha-1 cells, MLCs and MSCs form polarized monolayers with intercellular tight junctions and apical microvilli (30).…”

Section: Methodsmentioning

confidence: 99%

“…Cell Models-Human Mz-Cha-1 biliary cells (28) and mouse large (MLCs) and small (MSCs) cholangiocytes (29) derived from large and small intrahepatic bile ducts, respectively, and transformed via SV40 transfection were cultured as described previously (7,30). Each model system expresses phenotypic features of differentiated biliary epithelium, including receptors, signaling pathways, and ion channels, similar to those found in primary cells (7,29,30).…”

Section: Methodsmentioning

confidence: 99%

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Regulation of Purinergic Signaling in Biliary Epithelial Cells by Exocytosis of SLC17A9-dependent ATP-enriched Vesicles

Sathe

Woo

Kresge

et al. 2011

Journal of Biological Chemistry

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ATP in bile is a potent secretogogue, stimulating biliary epithelial cell (BEC) secretion through binding apical purinergic receptors. In response to mechanosensitive stimuli, BECs release ATP into bile, although the cellular basis of ATP release is unknown. The aims of this study in human and mouse BECs were to determine whether ATP release occurs via exocytosis of ATP-enriched vesicles and to elucidate the potential role of the vesicular nucleotide transporter SLC17A9 in purinergic signaling. Dynamic, multiscale, live cell imaging (confocal and total internal reflection fluorescence microscopy and a luminescence detection system with a high sensitivity charge-coupled device camera) was utilized to detect vesicular ATP release from cell populations, single cells, and the submembrane space of a single cell. In response to increases in cell volume, BECs release ATP, which was dependent on intact microtubules and vesicular trafficking pathways. ATP release occurred as stochastic point source bursts of luminescence consistent with exocytic events. Parallel studies identified ATP-enriched vesicles ranging in size from 0.4 to 1 m that underwent fusion and release in response to increases in cell volume in a protein kinase C-dependent manner. Present in all models, SLC17A9 contributed to ATP vesicle formation and regulated ATP release. The findings are consistent with the existence of an SLC17A9-dependent ATPenriched vesicular pool in biliary epithelium that undergoes regulated exocytosis to initiate purinergic signaling.Purinergic signaling has emerged as a dominant pathway regulating biliary secretion and bile formation. Released into bile by both hepatocytes and biliary epithelial cells (known as cholangiocytes) in response to mechanosensitive stimuli (cell swelling and flow/shear stress) (1-3), extracellular ATP activates P2 receptors in the apical membrane of targeted cholangiocytes, resulting in increases in [Ca 2ϩ ] i , activation of K ϩ (4, 5) and Cl Ϫ (6, 7) channels, and a robust secretory response (8). Recent studies suggest that even the classical model of biliary epithelial cell secretion wherein secretin stimulates Cl Ϫ secretion via increases in cAMP is mediated by a pathway regulated by ATP release and autocrine/paracrine stimulation of P2 receptors on the apical cholangiocyte membrane (9, 10). The cellular mechanism of biliary epithelial ATP release has not been identified. Two potential pathways exist: transporter/ channel-mediated or exocytosis of ATP-containing vesicles. Cholangiocytes express several ATP-binding cassette proteins, such as MDR-1 and the cystic fibrosis transmembrane conductance regulator (CFTR) 2 (11, 12), implicated in ATP release. However, the effect of MDR-1 on ATP release can be disassociated from p-glycoprotein-related substrate transport, suggesting that MDR-1 per se is not likely to function as an ATP channel (13). Similarly, despite provocative data that CFTR functions as a regulator of ATP release, many cells exhibit ATP release in the absence of apparent CFTR express...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Regulation of Purinergic Signaling in Biliary Epithelial Cells by Exocytosis of SLC17A9-dependent ATP-enriched Vesicles

Sathe

Woo

Kresge

et al. 2011

Journal of Biological Chemistry

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“…9) [583,584]. Both small and large cholangiocytes show mechanosensitive vesicular ATP release, but this is greater in small cholangiocytes [709].…”

Section: Biliary Ductmentioning

confidence: 99%

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

Burnstock

2013

Purinergic Signalling

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Purinergic signalling plays major roles in the physiology and pathophysiology of digestive organs. Adenosine 5′-triphosphate (ATP), together with nitric oxide and vasoactive intestinal peptide, is a cotransmitter in nonadrenergic, non-cholinergic inhibitory neuromuscular transmission. P2X and P2Y receptors are widely expressed in myenteric and submucous enteric plexuses and participate in sympathetic transmission and neuromodulation involved in enteric reflex activities, as well as influencing gastric and intestinal epithelial secretion and vascular activities. Involvement of purinergic signalling has been identified in a variety of diseases, including inflammatory bowel disease, ischaemia, diabetes and cancer. Purinergic mechanosensory transduction forms the basis of enteric nociception, where ATP released from mucosal epithelial cells by distension activates nociceptive subepithelial primary afferent sensory fibres expressing P2X3 receptors to send messages to the pain centres in the central nervous system via interneurons in the spinal cord. Purinergic signalling is also involved in salivary gland and bile duct secretion.

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“…Extracellular ATP, via the activation of cell surface P2 purinergic receptors, influences cell signaling, activation of transcription factors, and gene expression (5,18). In recent years, extracellular ATP is beginning to be recognized as a potential humoral factor influencing multiple liver functions in an autocrine and paracrine manner (58,70). We have previously shown that extracellular ATPmediated P2 purinergic receptor activation induces mitogenic signaling and hepatocyte proliferation of primary rat hepatocytes in vitro (67).…”

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confidence: 99%

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

Tackett

Sun

Mei

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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cellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2Ϫ/Ϫ) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24 -72 h) in response to 70% PH were impaired in P2Y2Ϫ/Ϫ mice. Interestingly, early induction of cytokines (TNF-␣, IL-6) and cytokine-mediated signaling (NF-B, STAT-3) were intact in P2Y2Ϫ/Ϫ remnant livers, uncovering the importance of cytokine-independent and nucleotidedependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2Ϫ/Ϫ mice were treated with ATP or ATP␥S for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH. extracellular ATP; P2Y2 purinergic receptors; partial hepatectomy; hepatocyte proliferation; liver regeneration LIVER REGENERATION IN RESPONSE to partial hepatectomy (PH) is a highly coordinated process involving a complex interplay of multiple humoral factors and integration of cell signaling in parenchymal and nonparenchymal cells (45). In response to PH, adult hepatocytes are "reprogrammed" to undergo cell cycle progression and proliferation until tissue restitution is achieved. The factor(s) that trigger cell cycle progression of hepatocytes in response to PH as well as cellular events that play a role in the reestablishment of quiescence upon the completion of liver growth are not well understood.In response to 70% PH, the remnant livers are subjected to elevated shear stress and trigger the release of factors believed to play key roles in the initiation of proliferative response in hepatocytes (1, 15, 60). Cellular stress including shear stress is a potent trigger for ATP release. Extracellular ATP, via the activation of cell surface P2 purinergic receptors, influences cell signaling, activation of transcription factors, and gene expression (5, 18). In recent years, extracellular ATP is begin...

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

Cited by 43 publications

References 28 publications

Regulation of Purinergic Signaling in Biliary Epithelial Cells by Exocytosis of SLC17A9-dependent ATP-enriched Vesicles

Regulation of Purinergic Signaling in Biliary Epithelial Cells by Exocytosis of SLC17A9-dependent ATP-enriched Vesicles

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy

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