The zinc sensing receptor, a link between zinc and cell signaling Academic Article uri icon


  • The zinc gradient across the plasma membrane may reach six orders of magnitude, as cytoplasmic Zn is tightly buffered by a variety of mechanisms (1). Specific binding sites for Zn are present on numerous proteins, including Zn fingers on transcription factors, that bind it with high affinity, and metallothioneins, to which the Zn is more loosely bound. Dynamic changes in extracellular Zn occur upon its release from cells in organs such as pancreas, brain, and salivary gland (2–4), while changes in intracellular Zn may result from oxidative stress (5,6). Such dynamic changes in Zn gradients and the availability of specific Zn binding domains suggest that Zn ions, once considered merely structural elements, are, in fact, important signaling molecules that influence many aspects of cell physiology. The signaling effects of Zn may be mediated by intracellular or extracellular Zn ions. It is generally accepted that an increase in free intracellular Zn is associated with cell death. For example, release of intracellular Zn, triggered by formation of reactive oxygen species (ROS) or by nitrosilation, induces proapoptotic molecules, e.g., p38, and activation of Kchannels leading to cell death (7,8). Chelation of intracellular Zn then, using a high affinity Zn chelator, could interfere with this process. Chelation of intracellular Zn, however, may remove zinc from intracellular metalloproteins, resulting in protein synthesis-dependent, caspase-3 mediated apoptosis (9). To protect cells from the consequences of a decrease in cellular zinc, changes in plasma Zn often precede the reduction of this ion within cells. Symptoms of zinc deficiency, therefore, particularly attenuation of cell proliferation, are observed long before changes in intracellular zinc are observed (10). Thus, sensing changes in extracellular Zn, and activation of signaling to regulate cell processes, before key components (e.g., zinc finger proteins) are affected, is essential. This Zn-sensing function might also provide protection against a sudden rise in intracellular Zn in tissues in which Zn is released during normal activity, e.g., in endocrine and exocrine glands or at glutamatergic synapses in the mammalian forebrain. Extracellular Zn indirectly activates cell signaling, by interacting with major membrane transporters and ion channels, most notably, the dopamine transporter, NMDA, glycine, GABA, and purinergic receptors (11–15). A high affinity binding site has also been

publication date

  • January 1, 2007