Homeostasis usually limits Cu transport from the gastrointestinal tract.
Differences among dietary species are largely eliminated at this step
(Windisch, 2002). A major pathway of Cu absorption is
mediated by transport proteins located in the intestinal brush-border
membrane that move these metals as inorganic divalent cations from the
(Windisch, 2002). The decrease in the
percentage of Cu absorbed when dietary intake increases is compatible
with a carrier-mediated transport process
(Wapnir, 1998). A saturable Cu transport system is expressed
in early maturity in rats
(Varada et al., 1993) and mice
et al., 2002b). In mice, Cu transport appears to be mediated
by Ctr1 as well as additional Cu transporter(s)
et al., 2002b).
modulating tripeptide glycyl-L-histidyl-L-lysine was found to bind Cu(II)
and was suggested to play a role in the transport of Cu(II) from blood
(Lau and Sarkar, 1981).
transport into tissues is probably dependent on the ion being delivered
to the cells, either in association with ceruloplasmin or an amino acid,
of which L-histidine is probably the most important
(Kataoka and Tavassoli, 1985).
erythrocyte Cl-bicarbonate anion exchanger can mediate Cu(II) uptake,
perhaps as Cu(OH)2Cl- and Cu(OH)2HCO3-
and Garay, 1990).
Cu(II) transport has been demonstrated in several in vitro preparations,
including the hepatocyte
Four genes have been reported to influence the cellular uptake and the delivery of Cu to specific cell compartments and proteins: 1) hCTR1, which regulates cellular uptake, 2) HAH1, which mediates transfer to Menkes and Wilson disease transporters, 3) CCS, which is related to Cu transfer to superoxide dismutase, and 4) hCOX17, which directs trafficking to mitochondrial cytochrome-c oxidase (Fu et al. 2003).
hCTR1 (analogous to yeast ctr1) and hCTR2 appear to be Cu
transporters. hCTR1 is expressed in human liver, brain and skeletal
(Zhou and Gitschier, 1997). Human Ctr1
(hCtr1) is a component of the Cu transport machinery at the plasma
membrane, is a ubiquitously expressed transmembrane protein. It transports Cu with high affinity in a time-dependent and
saturable manner and is metal-specific. hCtr1-mediated Cu transport is
energy-independent and stimulated by extracellular acidic pH and high K+
(Lee et al., 2002a). It is likely to be the mediator of cellular Cu uptake in human cells (Kuo et al. 2001; Lee et al. 2002; Moller et al. 2000; Zhou and Gitschier 1997).
Mammalian Cu chaperones include hCOX17, which is involved in Cu delivery to mitochondria and mitochondrial cytochrome-c oxidase , CCS, which delivers Cu to Cu/Zn superoxide dismutase, and HAH1, which transfers Cu to the Cu-transporting proteins that are critical for its efflux reviewed in (Camakaris, Voskoboinik, and Mercer 1999).
divalent metal transporter 1 (DMT-1) can transport Cu(II) (Gunshin et al., 1997).
protein is important to Cu homeostasis in mammalian cells. It functions
as a Cu-translocating P-type ATP-ase. Copper transport was observed only
under reducing conditions suggesting MNK transports Cu(I)
(Voskoboinik et al., 1998).
CopA is a
putative copper-translocating P-type ATPase that has been shown to be
involved in copper resistance in Escherichia coli. It exhibited
ATP-coupled Cu efflux, presumably of Cu(I). It may be a carrier that is
similar to the Cu carriers related to Menkes and Wilson diseases
(Rensing et al., 2000).
has been presented that multidrug resistance-associated protein 2 (MRP2)
mediates the biliary transport of Cu glutathione complexes
mechanism for Cu transport from lysosomes to bile is not clear. Carriers
implicated have included small peptides
(Evans and Cornatzer, 1971;
and Owen, 1973;
Martin et al., 1986), amino acids
(Evans and Cornatzer, 1971;
Martin et al., 1986), bile acids
(Lewis, 1973), metallothionein
and Bremner, 1984), and macromolecular complexes
(Gollan and Deller, 1973;
and Owen, 1973;
Kressner et al., 1984). Some of the intracellular Cu may be
excreted into bile in a microtubule-dependent fashion, possibly via
(Harada et al., 1993).
The Cu-ATPases, ATP7A, and ATP7B play an important role in the physiological regulation of Cu. They are members of the P-type ATPases family of cation transporters (Vulpe et al. 1993; Bull et al. 1993). They are Cu efflux pumps. Copper transport to the brain requires a mechanism for transport across the blood brain epithelium. This is blocked in Menkes disease, where there are mutations of ATP7A, suggesting ATP7A is the transporter involved (Kodama 1993) causing the Cu deficiency condition Menkes disease. ATP7B is thought to deliver Cu to the bile when Cu levels in the liver start to rise. It also supplies Cu to the secreted cuproenzyme, ceruloplasmin (Yoshida et al. 1995). Mutations of ATP7B produce Wilson disease (Mercer and Llanos 2003).
ATP7B transports Cu into milk (Rauch 1983).
It has been shown that Cu efflux from murine cerebrovascular endothelial
cells is blocked by an agent that is a potential inhibitor of ATP7A
(Qian et al., 1998). These
results have been interpreted to suggest that Menkes disease is due to
lack of Cu transport into the brain at the blood-brain barrier by the
mutated ATP7A in the brain cerebrovascular endothelial cells
(Qian et al, 1998).
ATP7A has been shown to mediate Cu efflux from murine BCECs
(Qian et al., 1998).
Link to Transporters Periodic Table
Link to Database Index