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Abstract
The bile acid-sensitive ion channel (BASIC) is a member of the Deg/ENaC family of ion channels that is activated by bile acids. Despite the identification of cholangiocytes in the liver and unipolar brush cells in the cerebellum as sites of expression, the physiological function of BASIC in these cell types is not yet understood. Here we used a cholangiocyte cell line, normal rat cholangiocytes (NRCs), which expresses BASIC to study the role of the channel in epithelial transport using Ussing chamber experiments. Apical application of bile acids induced robust and transient increases in transepithelial currents that were carried by Na+ and partly blocked by the BASIC inhibitor diminazene. Genetic ablation of the BASIC gene in NRC using a CRISPR-cas9 approach resulted in a decrease of the bile acid-mediated response that matched the diminazene-sensitive current in NRC WT cells, suggesting that cholangiocytes respond to bile acids with a BASIC-mediated Na+ influx. Taken together, we have identified BASIC as a component of the cholangiocyte transport machinery, which might mediate a bile acid-dependent modification of the bile and thus control bile flux and composition.
Highlights
The bile acid-sensitive ion channel (BASIC) is probably the least studied mammalian member of the degenerin/epithelial Na+ channel (Deg/epithelial N a+ channel (ENaC)) family of ion channels [40]
To address whether BASIC is involved in ion transport processes in cholangiocytes, we used normal rat cholangiocytes (NRCs) [35]
NRCs maintained an epithelial-like, cholangiocyte phenotype when grown on cell culture inserts with 0.4μm pore size coated with rat tail collagen (Fig. 1A) and cells developed a moderate transepithelial electrical resistance (TEER) of approximately 400–600 Ω/cm2 after 2 weeks of culturing (Fig. 1B), which is in line with previous results [35]
Summary
The bile acid-sensitive ion channel (BASIC) is probably the least studied mammalian member of the degenerin/epithelial Na+ channel (Deg/ENaC) family of ion channels [40]. Deg/ENaCs share several structural, electrophysiological, and pharmacological features [16]. Each channel consists of three subunits, which are composed of two transmembrane domains and linked by a large extracellular domain, N-terminal and C-terminal domains protruding into the cytosol [4, 15]. Deg/ENaCs are voltage-independent and mainly conduct monovalent cations with different selectivities [16]. A common inhibitor of Deg/ENaCs is the diuretic amiloride [16], ASICs and BASIC are inhibited by diminazene, a diarylamidine that is used as an antiprotozoal drug in veterinary medicine [7, 37].
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