Crosstalk of the group IIa and IIb metals calcium and zinc in cellular signaling.

L ife has harnessed the functional potential of many metal ions and thereby bridged the boundaries between organic and inorganic chemistry. A case in point here is zinc, which is essential for growth and development. As a constituent of proteins, zinc performs critical cellular functions (1). Its great versatility in catalysis is used in hundreds of enzymes of all six classes (2). In zinc finger proteins—a generic term for several coordination types in thousands of proteins—it has primarily a structural role in organizing protein domains for the recognition of other proteins, nucleic acids, and lipids (3, 4). A third function, regulation, which requires a dynamic state of the zinc ion, is less well established and is the subject of this commentary. In a recent issue of PNAS, Hershfinkel et al. (5) suggested that a ‘‘zinc-sensing receptor’’ exists on the plasma membrane of HT-29 cells. They challenged these colon cancer cells with zinc and followed cellular calcium with the fluorophore Fura-2. Micromolar concentrations of extracellular zinc (Zn21)—but not of other metal ions—mobilize intracellular calcium, [Ca]i, by releasing it from its store in the endoplasmic reticulum (ER). Because intracellular zinc does not increase, the authors suspect that zinc acts at the cell membrane. Further studies on the possible signal transduction pathway implicate the involvement of a Gprotein, phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP3) receptors on the ER membrane (Fig. 1, pathway A). The effect of zinc on the rise of calcium was confirmed in other human cells, e.g., salivary gland cells and primary keratinocytes. Last but not least, the authors show that the action of zinc is upstream from the known calcium-stimulated Na1yH1 antiporter, which controls cellular pH. They conclude that such a ‘‘zinc-sensing receptor’’ might provide a missing link between extracellular zinc and regulation of cellular processes. Previously, a rise of cytosolic calcium on stimulation of cells with metal ions had been studied mainly in the context of toxic actions of metal ions (6–8). Thus, Smith and coworkers (9) had already proposed a similar mechanism for cadmium and other heavy metal ions, invoking an ‘‘orphan receptor,’’ G-protein-coupled activation of PLC, and subsequent IP3-triggered release of calcium from its ER store. The effect of cadmium was inhibited by zinc, however (6, 8). Jan et al. (10) observed that zinc increases resting cytosolic calcium levels in canine kidney cells. They attributed the rise in calcium to an influx of extracellular calcium, because the effect of zinc was abolished when calcium in the medium was removed. This observation differs from the one made by Hershfinkel et al. (5), where zinc is stimulatory even when calcium-free Ringer solution was used. McNulty and Taylor (11) also detected a rise of cellular calcium on treatment of hepatocytes with various metals. They concluded that, among the metals tested, zinc ought to be the physiological substrate for this ‘‘heavy metal receptor.’’ All of these studies indicate that different metal ions affect cellular calcium homeostasis differently, and that even for a given metal, e.g., zinc, intracellular calcium can be influenced through several mechanisms. The present work is intriguing because it draws attention to a possibly significant role of transitionyheavy metal ions in cellular signaling and because it could provide a unifying theme for novel actions of metal ions in biology. If extracellular metal ions have effects through a universal signal such as mobilization of intracellular calcium, this would have wide ramifications for physiology, pathology, and toxicology. Yet, many questions remain. The possible events at the plasma membrane in particular deserve further scrutiny. In none of the above studies has a receptor for the metal ion been identified. Further work awaits the characterization of the zinc-sensitive re-