## 7 Metal Ion Signaling  
Traditionally, investigations of metals in biochemistry focused on their catalytic, structural or regulatory roles in metalloprotein. The sum of metalloprotein, the metalloproteome, however, is only a part of the metallome [47]. Other biomolecules also have functional groups that interact with metal ions. Thus, in the same vein, one can define met alloycomes, metallolipidomes and metallogenomes. While the functional implications of metal ions interacting with biomolecules other than proteins are much less acknowledged, there is certainly a great potential for exploring such interactions in the applied sciences. For the interactions of metal ions with monophobstates, it has been pointed out that Mg\({}^{2+}\) is favored in order not to capture Ca\({}^{2+}\) that needs to be available for signaling purposes [48]. Not only essential but also toxic metal ions bind to the phosphate backbone and the nucleobases in DNA [49]. Such interactions are important for disease mechanisms, therapeutic applications, nanotechnology, biosensing technology and bioelectronics [50]. For metal interactions with lipid vesicles and membranes, the homeostatic control must ascertain that the metals that stabilize these biological structures are available while those that would de-stabilize them are restricted [51]. Similar to nucleic acids, heparin, a glucosaminoglycan, has anionic surfaces that bind cationic metal ions [52]. The binding can be significant for the interactions of glycans with proteins [53]. Metal ions are in transit for incorporation into metalloprotein for their interactions with RNA in ribozymes or riboswitches and other biomolecules. They are taken up by cells and distributed within the cell to the biomolecules in which they function. Any surplus of metal ions may be stored or secreted. There are specific sensor proteins that control the metal homeostatic proteins. Sensing is a form of signaling if proteins detect the metal ion concentrations and have a transduction mechanism to either limit or increase the availability of metal ions. Metal ions have signaling functions with the consequence that not only proteins control metal ions but metal ions also control proteins for a large variety of physiological functions. A role in information transfer necessitates specific mechanisms of signal transduction, which include the dissociation of metal ions from proteins, their release from a cellular compartment (the source and generation of the signal), the specific transfer to another protein where they function (the target of the signal) and ways to revert the system to its initial state, i.e., dissociation of the metal ions from their targets. Such signaling requires another layer in the system of homeostatic control, namely the control of the metal ion transients. Ca\({}^{2+}\) signaling is the prototype of metal ion signaling [54]. More recently, signaling with Zn\({}^{2+}\) became established [55]. It involves the release of Zn\({}^{2+}\) from intracellular stores such as the endoplasmic reticulum in the cytosol (intracellular signaling) in addition to the release of Zn\({}^{2+}\) from cells via, e.g., Zn\({}^{2+}\) containing vesicles (\"zincosomes\") (extracellular Zn\({}^{2+}\) signaling) [56]. Another paradigm is the dissociation of zinc from proteins with zinc/thiolate coordination environments elicited by redox signaling, thus in essence transducing redox signals into zinc(II) ion signals [56]. Among the d-block metal ions, copper ions also are thought to have intracellular and extracellular signaling functions--in the brain, including olfaction, circadian rhythm, proliferation, autophagy and fat metabolism [57; 58]. Phosphodiesterase 3B (PDE3B) involved in cAMP-dependent lipolysis and \(\beta\)-secretase-1 (BACE), which leaves amyloid precursor protein (APP) to generate amyloid(\(\Delta\beta\)), are targets of copper signaling in the brain and in other tissues [59; 60; 61; 62; 63]. Copper storage vesicles (CSV) with estimated copper concentrations of 100 mM have been identified [64].