Copper entry into human cells: progress and unanswered questions.

In this brief review we summarize what is known about the role of hCTR1 in mediating the entry of copper into human cells. There is a body of information that clearly identifies this protein as being a major source (though not the only source) of copper entry into human cells, and thus a crucial element of copper homeostasis. However, much remains that is poorly understood and key aspects of the physiological roles of hCTR1 and its regulation are only superficially appreciated. The particular characteristics of a transport process that in vivo involves the binding, transmembrane transport and release of a substrate that is not present in a free form in the intracellular or extracellular compartments poses particular challenges that are not encountered in the transport of more familiar physiologically important metal cations. Thus much of what we have learned about the more commonly encountered transported ions provides an inadequate model for studies of copper homeostasis. In this article we review progress made and identify the major questions that need to be resolved before an adequate description is attained of how copper entry into human cells is mediated and regulated by hCTR1.