Populations of hepatocytes in primary culture were loaded with fura 2 and the effects of extracellular heavy-metal ions were examined under conditions that allowed changes in fura 2 fluorescence (R340/360, the ratio of fluorescence recorded at 340 and 360 nm) to be directly attributed to changes in cytosolic free [Ca2+] ([Ca2+]i). In Ca2+-free media, Ni2+ [EC50 (concentration causing 50% stimulation) ≈ 24±9 μM] caused reversible increases in [Ca2+]i that resulted from mobilization of the same intracellular Ca2+ stores as were released by [Arg8]vasopressin. The effects of Ni2+ were not mimicked by increasing the extracellular [Mg2+], by addition of MnCl2, CoCl2 or CdCl2 or by decreasing the extracellular pH from 7.3 to 6.0; nor were they observed in cultures of smooth muscle, endothelial cells or pituitary cells. CuCl2 (80 μM), ZnCl2 (80 μM) and LaCl3 (5 mM) mimicked the ability of Ni2+ to evoke Ca2+ mobilization. The response to La3+ was sustained even in the absence of extracellular Ca2+, probably because La3+ also inhibited Ca2+ extrusion. Although Ni2+ entered hepatocytes, from the extent to which it quenched fura 2 fluorescence the free cytosolic [Ni2+] ([Ni2+]i) was estimated to be < 5 nM at the peak of the maximal Ni2+-evoked Ca2+ signals and there was no correlation between [Ni2+]i and the amplitude of the evoked increases in [Ca2+]i. We conclude that extracellular Ni2+, Zn2+, Cu2+ and La3+, but not all heavy-metal ions, evoke an increase in [Ca2+]i in hepatocytes by stimulating release of the hormone-sensitive intracellular Ca2+ stores and that they may do so by interacting with a specific cell-surface ion receptor. This putative ion receptor may be important in allowing hepatocytes to contribute to regulation of plasma heavy-metal ions and may mediate responses to Zn2+ released into the portal circulation with insulin.
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Research Article|
April 26 1999
Extracellular heavy-metal ions stimulate Ca2+ mobilization in hepatocytes
Tracy J. MCNULTY;
Tracy J. MCNULTY
1Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, U.K.
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Colin W. TAYLOR
Colin W. TAYLOR
1
1To whom correspondence should be addressed (e-mail cwt1000@cam.ac.uk).
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Publisher: Portland Press Ltd
Received:
October 12 1998
Revision Received:
January 06 1999
Accepted:
February 05 1999
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1999
1999
Biochem J (1999) 339 (3): 555–561.
Article history
Received:
October 12 1998
Revision Received:
January 06 1999
Accepted:
February 05 1999
Citation
Tracy J. MCNULTY, Colin W. TAYLOR; Extracellular heavy-metal ions stimulate Ca2+ mobilization in hepatocytes. Biochem J 1 May 1999; 339 (3): 555–561. doi: https://doi.org/10.1042/bj3390555
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