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Copper transporter 1 (CTR1) and the mechanisms of Cu uptake from blood plasma proteins by mammalian cells

CTR1 is the only specific Cu uptake transporter so far identified in mammalian cells. However in some cell types, Ag(I) (which inhibits CTR1) does not impede Cu uptake from plasma proteins or the histidine complex. To further test the importance of CTR1, we measured rates of uptake in cells with/without knockdown and knockout. siRNA knockdown (65–85%) of CTR1 mRNA made no difference to rates of Cu(II) uptake from human albumin and alpha2macroglobulin by human mammary epithelial and hepatic cell lines. Uptake of Cu from Cu(I)‐histidine or Cu(II)‐mouse albumin by mouse embryonic fibroblasts was only ~15% less in Ctr1‐null versus wild type cells (kindly provided by Dennis Thiele). Maximum rates of uptake from the his complex were ~10× greater for Cu(I) than Cu(II). The kinetics of Cu(II) uptake from mouse albumin were closer to those of Cu(I)‐his (Vmax 14 pmol/min/mg cell protein; Km 1 uM), while those from human albumin were similar to Cu(II)‐his (Vmax 4–6, Km 2–4.5). Cell surface Cu(II) and Fe(III) reductase activity was detected; but Fe(III) failed to inhibit uptake from Cu(II)‐albumin. In the Ctr1 null cells, there also was some inhibition by Ag(I). It is concluded that mammalian cells contain at least one additional Ag(I)‐inhibitable Cu transporter, that prefers Cu(I), probably receiving it upon reduction of Cu(II) by a cell surface reductase. Supported by HHMI and USPHS Grant RO1 HD46949.