Focus Issue: Metals in Biology: Coin for the Signaling Realm?

From the time of the protoscientists who learned to extract metals from ores and mix copper with tin, catapulting our ancestors from the Neolithic to the Bronze Age, metals have been an integral part of our lives. The alchemists' attempts to transform lead and other "base" metals to gold laid the foundations for modern chemistry and, today, metals provide the skeletons of our skyscrapers, constitute a medium for our currency, and add color to our lives in pigments and glazes. Metals are also critical to our biology, and the current issues of Science and Science's STKE bring together a series of articles on metals in biology and in the environment. Science's STKE highlights two metals with essential biological roles in signaling: iron and zinc. Iron, which is required for human respiration both during oxygen transport by hemoglobin and during oxidative phosphorylation, is also implicated in cytotoxic effects of macrophage-produced nitric oxide (NO); zinc, which is an important structural element in many enzymes and transcription factors, is beginning to be recognized as a signaling messenger. As discussed in the Science article by Finney and O'Halloran, various transition metals--including zinc, copper, and iron--are not only essential components of proteins but can also be cytotoxic. As a rule, these metals are tightly regulated at very low free concentrations inside cells, necessitating an intricate array of transporters, metal sensors, and diffusible protein chaperones to guide them to their protein targets. In an STKE Perspective, Bouton and Drapier discuss the complex effects of NO on two iron regulatory proteins (IRP1 and IRP2) and, consequently, on iron uptake and metabolism. NO, produced secondary to inflammatory responses, promotes the conversion of IRP1 from an aconitase to an RNA binding regulator of transferrin receptor and ferritin synthesis and simultaneously decreases the expression of IRP2. Compared to target cells that respond to macrophage-produced NO, macrophages respond differently to NO than would be expected based on the effects of IRP activity alone. Bouton and Drapier discuss the basis for these differences in cellular response to NO with regard to iron handling and cytotoxicity. For more on NO signaling, see the Review by Lane et al ., the Protocol by Jaffrey and Snyder, and the Perspective by Helmann in the STKE Archives. Among signaling molecules, the alkaline earth metal calcium has long reigned as the prima donna of metals; zinc is now beginning to take the stage as a signaling star as well. Zinc's emerging role as both an intercellular and intracellular signal is described in two complementary STKE Perspectives. This role depends upon an exception to the above rule of extremely low concentrations of free (or loosely bound) zinc: A pool of chelatable zinc that is sequestered in presynaptic vesicles in some regions of the brain and released following physiological stimuli. Li et al . discuss research that implicates zinc released from hippocampal mossy fibers in the heterosynaptic regulation of N -methyl-D-aspartate (NMDA) receptors and as a trans-synaptic second messenger that enters postsynaptic neurons to modulate various signal transduction pathways. Frederickson describes the zinc-sensitive dyes--from dithizonate to the new fluorescence resonance energy transfer (FRET)-based sensors--and imaging techniques that freed zinc from its protein shackles by identifying sequestered pools of releasable zinc in synaptic vesicles and secretory granules that can be released into the extracellular space. The STKE Archives are rich in articles related to calcium signaling and various imaging techniques. For example, calcium signaling and gene regulation in neurons is the topic of two Perspectives (by Dolmetsch and by Impey and Goodman). Frequency-dependent calcium signaling in plants is the topic of the Review by Allen and Schroeder. The Perspective by Gaits and Hahn in the STKE Archives describes the various applications of biosensors, including the use of biosensors to perform FRET analysis. Calcium imaging methods can be found in the Protocols by Fiala and Spall and Shimonozo et al . As new methods are developed and novel regulatory mechanisms are uncovered, more metals may become recognized as players in the signaling realm. Featured in this Focus Issue Related Resources