Interactions of Cadmium with Signaling Molecules

Abstract

Cadmium has no known function in higher organisms, which have evolved in an essentially cadmium-free environment until the last several hundred years of industrial activity. Thus, cadmium’s interactions with biological molecules are generally fortuitous and determined by its inorganic chemistry. In biological systems, it exists exclusively in the Cd²⁺ state as the only ionized form, and it is somewhat unique in showing properties both of a Ca²⁺ mimic (by virtue of its ionic radius) and of a “soft” sulfur-binding ion (with polarizable d electrons). We review here the interactions of Cd²⁺ with cellular signaling systems; these are broad and non-specific, and result in interactions with both Ca²⁺ signaling and thiol-dependent redox systems, sometimes with ambiguous consequences. The chapter focuses on interactions more than consequences, as the latter are often very complex in origin, but can sometimes be simplified by collecting some of the interactions that have been observed. We discuss some of the general effects of Cd²⁺ on cellular Ca²⁺ levels, with signaling implications, and also some of the major interactions of Cd²⁺ with Ca²⁺ binding sites in proteins. A good part of our discussion is of effects of Cd²⁺ on signaling pathways through kinase activation, phosphatase inhibition, modulation of second messengers, and effects on levels of growth factors and transcription factors. It will be seen that there is a lot of empirical data here that are only partially understood on the basis of Cd²⁺ chemistry. Cadmium regulation of thiol-dependent redox chemistry is also discussed, and some new directions in redox sensing are suggested.