Interplay of calcium and cadmium in mediating cadmium toxicity

The environmentally important toxic metal, cadmium, exists as the Cd(2+) ion in biological systems, and in this state structurally resembles Ca(2+). Thus, although cadmium exerts a broad range of adverse actions on cells by virtue of its propensity to bind to protein thiol groups, it is now well appreciated that Cd(2+) participates in a number of Ca(2+)-dependent pathways, attributable to its actions as a Ca(2+) mimetic, with a central role for calmodulin, and the Ca(2+)/calmodlin-dependent protein kinase II (CaMK-II) that mediates effects on cytoskeletal dynamics and apoptotic cell death. Cadmium interacts with receptors and ion channels on the cell surface, and with the intracellular estrogen receptor where it binds competitively to residues shared by Ca(2+). It increases cytosolic [Ca(2+)] through several mechanisms, but also decreases transcript levels of some Ca(2+)-transporter genes. It initiates mitochondrial apoptotic pathways, and activates calpains, contributing to mitochondria-independent apoptosis. However, the recent discovery of the role CaMK-II plays in Cd(2+)-induced cell death, and subsequent implication of CaMK-II in Cd(2+)-dependent alterations of cytoskeletal dynamics, has opened a new area of mechanistic cadmium toxicology that is a focus of this review. Calmodulin is necessary for induction of apoptosis by several agents, yet induction of apoptosis by Cd(2+) is prevented by CaMK-II block, and Ca(2+)-dependent phosphorylation of CaMK-II has been linked to increased Cd(2+)-dependent apoptosis. Calmodulin antagonism suppresses Cd(2+)-induced phosphorylation of Erk1/2 and the Akt survival pathway. The involvement of CaMK-II in the effects of Cd(2+) on cell morphology, and particularly the actin cytoskeleton, is profound, favouring actin depolymerization, disrupting focal adhesions, and directing phosphorylated FAK into a cellular membrane. CaMK-II is also implicated in effects of Cd(2+) on microtubules and cadherin junctions. A key question for future cadmium research is whether cytoskeletal disruption leads to apoptosis, or rather if apoptosis initiates cytoskeletal disruption in the context of Cd(2+).