NDLI: Blocking swelling-activated chloride current inhibits mouse liver cell proliferation

Content Provider	PubMed Central
Author	Wondergem, Robert Gong, Wei Monen, Scott H. Dooley, Sean N. Gonce, Joel L. Conner, Tracy D. Houser, Molly Ecay, Tom W. Ferslew, Kenneth E.
Copyright Year	2001
Abstract	A non-transformed mouse liver cell line (AML12) was used to show that blocking swelling-activated membrane Cl− current inhibits hepatocyte proliferation. Two morphologically distinguishable cell populations exhibited distinctly different responses to hypotonic stress. Hypotonic stress (from 280 to 221 mosmol kg−1) to rounded, dividing cells activated an ATP-dependent, outwardly rectifying, whole-cell Cl− current, which took 10 min to reach maximum conductance. A similar anionic current was present spontaneously in 20 % of the dividing cells. Hypotonic stress to flattened, non-dividing cells activated no additional current. The Eisenman halide permeability sequence of swelling-activated anionic current in the dividing cells was SCN− > I− > Br− > Cl− > gluconate. Addition of either 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS), 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), tamoxifen or mibefradil inhibited swelling-activated anionic current. Hyperosmolarity by added sucrose inhibited the spontaneous anionic current in dividing cells. Added Cl− channel blockers NPPB (IC50= 40 μm), DIDS (IC50= 31 μm), tamoxifen (IC50= 1.3 μm) and mibefradil (IC50= 7 μm) inhibited proliferative growth of AML12 as determined by cell counts over 4 days or by protein accumulation over 2 days. Only the inhibitory effects of NPPB and mibefradil reversed with the drug washout. Hyperosmolarity by added sucrose (50 and 100 mm) also inhibited cell proliferation. Of the hydrophobic inhibitors neither NPPB at 40 μm nor tamoxifen at 1.3 μm, added for 48 h, reduced cellular ATP; however, DIDS at 31 μm significantly reduced cellular ATP with an equivalent increase in cellular ADP. We conclude that those membrane Cl− currents that can be activated by hypotonic stress are involved in mechanisms controlling liver cell growth, and that NPPB, tamoxifen and mibefradil at their IC50 for growth do not suppress the metabolism of mouse hepatocytes.
Related Links	http://dx.doi.org/10.1111/j.1469-7793.2001.0661e.x
Ending Page	672
Page Count	12
Starting Page	661
File Format	PDF
ISSN	00223751
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 3
Volume Number	532
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2001-05-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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