PMID:18024594

Citation	Gradilone, SA, Masyuk, AI, Splinter, PL, Banales, JM, Huang, BQ, Tietz, PS, Masyuk, TV and Larusso, NF (2007) Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion. Proc. Natl. Acad. Sci. U.S.A. 104:19138-43
Abstract	Cholangiocytes, epithelial cells lining the biliary tree, have primary cilia extending from their apical membrane into the ductal lumen. Although important in disease, cilia also play a vital role in normal cellular functions. We reported that cholangiocyte cilia are sensory organelles responding to mechanical stimuli (i.e., luminal fluid flow) by alterations in intracellular Ca(2+) and cAMP. Because cholangiocyte cilia are also ideally positioned to detect changes in composition and tonicity of bile, we hypothesized that cilia also function as osmosensors. TRPV4, a Ca(2+)-permeable ion channel, has been implicated in signal transduction of osmotic stimuli. Using purified rat cholangiocytes and perfused intrahepatic bile duct units (IBDUs), we found that TRPV4 is expressed on cholangiocyte cilia, and that hypotonicity induces an increase in intracellular Ca(2+) in a TRPV4-, ciliary-, and extracellular calcium-dependent manner. The osmosensation of luminal tonicity by ciliary TRPV4 induces bicarbonate secretion, the main determinant of ductal bile formation, by a mechanism involving apical ATP release. Furthermore, the activation of TRPV4 in vivo, by its specific agonist, 4alphaPDD, induces an increase in bile flow as well as ATP release and bicarbonate secretion. Our results suggest that cholangiocyte primary cilia play an important role in ductal bile formation by acting as osmosensors.
Links	PubMed PMC2141921 Online version:10.1073/pnas.0705964104
Keywords	Adenosine Triphosphate/metabolism; Animals; Bicarbonates/metabolism; Bile/metabolism; Bile/secretion; Bile Ducts, Intrahepatic/cytology; Bile Ducts, Intrahepatic/metabolism; Calcium Signaling; Cilia/metabolism; Hydrogen-Ion Concentration; Hypotonic Solutions/pharmacology; Male; Osmolar Concentration; RNA, Messenger/biosynthesis; RNA, Small Interfering/pharmacology; Rats; Rats, Sprague-Dawley; TRPV Cation Channels/biosynthesis; TRPV Cation Channels/genetics; TRPV Cation Channels/physiology; Water/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:TRPV4		GO:0031513: cilium	ECO:0000314:		C		Figure 2: They found that TRPV4 is expressed in cholangiocyte cilia	complete

References

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