Cadmium and cellular signaling cascades: To be or not to be?

The cellular effects of the toxic metal cadmium (Cd) are manifold. A large proportion of the cellular reactions affected by ionic Cd 21 ire mediated by cellular signaling cascades. The aim of this review is to provide a principal understanding of the known physiological signaling cascades, which are recruited by Cd2+, and to highlight the fact that Cd 21, similarly to other toxic metals, disrupts physiological signal transduction. In principle, second messengers are generated at the time of receptor activation, are short-lived, and act specifically in space and time through non-covalent binding on effectors to transiently alter their activity. Signaling dysregulation induced by Cd2+ is reflected by a permanent disruption of transducing modules, resulting in low and/or elevated and constant levels of second messengers, which overwhelm the control mechanisms of signaling. This disturbs physiological cellular functions, gene transcription and regulation and may result in cell death and/or stress-induced adaptation and survival as well as carcinogenesis. The impact of Cd2+ on Ca2+-, cAMP-, NO-, ROS-, MAP-kinase-, PKB/Akt-, nuclear factor-kappa B-, and developmental signaling is critically discussed. The hierarchical as well as cooperative and integrative character of signaling cascades activated by Cd2+ is illustrated in the kidney proximal tubule, a major target of Cd2+ toxicity. This review also aspires to pinpoint new avenues of research that may contribute to a more differentiated view of the complex mechanisms underlying Cd2+ toxicity in target tissues and eventually lead to rationales and strategies for prevention and therapy of Cd2+ toxicity. (c) 2009 Elsevier Inc. All rights reserved.