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Effect of divalent heavy metals on epithelial Na⁺ channels in A6 cells

Departments of ¹Physiology and ²Pediatrics and ³The Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia

Submitted 2 January 2007 ; accepted in final form 6 April 2007

To better understand how renal Na⁺ reabsorption is altered by heavy metal poisoning, we examined the effects of several divalent heavy metal ions (Zn²⁺, Ni²⁺, Cu²⁺, Pb²⁺, Cd²⁺, and Hg²⁺) on the activity of single epithelial Na⁺ channels (ENaC) in a renal epithelial cell line (A6). None of the cations changed the single-channel conductance. However, ENaC activity [measured as the number of channels (N) x open probability (P_o)] was decreased by Cd²⁺ and Hg²⁺ and increased by Cu²⁺, Zn²⁺, and Ni²⁺ but was not changed by Pb²⁺. Of the cations that induced an increase in Na⁺ channel function, Zn²⁺ increased N, Ni²⁺ increased P_o, and Cu²⁺ increased both. The cysteine modification reagent [2-(trimethylammonium)ethyl]methanethiosulfonate bromide also increased N, whereas diethylpyrocarbonate, which covalently modifies histidine residues, affected neither P_o nor N. Cu²⁺ increased N and stimulated P_o by reducing Na⁺ self-inhibition. Furthermore, we observed that ENaC activity is slightly voltage dependent and that the voltage dependence of ENaC is insensitive to extracellular Na⁺ concentration; however, apical application of Ni²⁺ or diethylpyrocarbonate reduced the channel voltage dependence. Thus the voltage sensor of Xenopus ENaC is different from that of typical voltage-gated channels, since voltage appears to be sensed by histidine residues in the extracellular loops of ENaC, rather than by charged amino acids in a transmembrane domain.

divalent cations; single-channel recording; sodium self-inhibition

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