Sodium-dependent copper uptake across epithelia: a review of rationale with experimental evidence from gill and intestine

Biochim Biophys Acta. 2002 Nov 13;1566(1-2):104-15. doi: 10.1016/s0005-2736(02)00590-4.


The paper reviews the evidence for apparent sodium-dependent copper (Cu) uptake across epithelia such as frog skin, fish gills and vertebrate intestine. Potential interactions between Na(+) and Cu during transfer through epithelial cells is rationalized into the major steps of solute transfer: (i) adsorption on to the apical/mucosal membrane, (ii) import in to the cell (iii) intracellular trafficking, and (iv) export from the cell to the blood. Interactions between Na(+) and Cu transport are most likely during steps (i) and (ii). These ions have similar mobilities (lambda) in solution (lambda, Na(+), 50.1; Cu(2+), 53.6 cm(2) Int. ohms(-1) equiv(-1)); consequently, Cu(2+) may compete equally with Na(+) for diffusion to membrane surfaces. We present new data on the Na(+) binding characteristics of the gill surface (gill microenvironment) of rainbow trout. The binding characteristics of Na(+) and Cu(2+) to the external surface of trout gills are similar with saturation of ligands at nanomolar concentrations of solutes. At the mucosal/apical membrane of several epithelia (fish gills, frog skin, vertebrate intestine), there is evidence for both a Cu-specific channel (CTR1 homologues) and Cu leak through epithelial Na(+) channels (ENaC). Cu(2+) slows the amiloride-sensitive short circuit current (I(sc)) in frog skin, suggesting Cu(2+) binding to the amiloride-binding site of ENaC. We present examples of data from the isolated perfused catfish intestine showing that Cu uptake across the whole intestine was reduced by 50% in the presence of 2 mM luminal amiloride, with 75% of the overall inhibition attributed to an amiloride-sensitive region in the middle intestine. Removal of luminal Na(+) produced more variable results, but also reduced Cu uptake in catfish intestine. These data together support Cu(2+) modulation of ENaC, but not competitive entry of Cu(2+) through ENaC. However, in situations where external Na(+) is only a few millimoles (fish gills, frogs in freshwater), Cu(2+) leak through ENaC is possible. CTR1 is a likely route of Cu(2+) entry when external Na(+) is higher (e.g. intestinal epithelia). Interactions between Na(+) and Cu ions during intracellular trafficking or export from the cell are unlikely. However, effects of intracellular chloride on the Cu-ATPase or ENaC indicate that Na(+) might indirectly alter Cu flux. Conversely, Cu ions inhibit basolateral Na(+)K(+)-ATPase and may increase [Na(+)](i).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amiloride / pharmacology
  • Animals
  • Anura
  • Binding, Competitive
  • Catfishes
  • Cation Transport Proteins*
  • Cell Membrane / metabolism
  • Copper / blood
  • Copper / metabolism*
  • Copper Transporter 1
  • Down-Regulation
  • Epithelium / metabolism*
  • Gills / metabolism*
  • Intestinal Absorption / drug effects
  • Intestinal Mucosa / metabolism*
  • Ion Transport / drug effects
  • Membrane Potentials
  • Membrane Proteins / metabolism
  • Oncorhynchus mykiss
  • Sodium / analysis
  • Sodium / blood
  • Sodium / metabolism*
  • Sodium Channels / metabolism
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors


  • Cation Transport Proteins
  • Copper Transporter 1
  • Membrane Proteins
  • Sodium Channels
  • Copper
  • Amiloride
  • Sodium
  • Sodium-Potassium-Exchanging ATPase