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Our understanding of the roles played by zinc in the physiological and pathological functioning of the brain is rapidly expanding. The increased availability of genetically modified animal models, selective zinc-sensitive fluorescent probes, and novel chelators is producing a remarkable body of exciting new data that clearly establishes this metal ion as a key modulator of intracellular and intercellular neuronal signaling. In this Mini-Symposium, we will review and discuss the most recent findings that link zinc to synaptic function as well as the injurious effects of zinc dyshomeostasis within the context of neuronal death associated with major human neurological disorders, including stroke, epilepsy, and Alzheimer’s disease.

Summary Zn2+ that is co-released with glutamate from mossy fiber terminals can influence synaptic function. Here, we demonstrate that synaptically released Zn2+ activates a selective post-synaptic Zn2+-sensing receptor (ZnR) in the CA3 region of the hippocampus. ZnR activation induced intracellular release of Ca2+, as well as phosphorylation of extracellular-regulated kinase and Ca2+/calmodulin kinase. ZnR-mediated Ca2+ rises were dramatically attenuated in slices from mice lacking vesicular Zn2+. In addition, knockdown of the expression of the orphan G-protein coupled receptor GPR39 attenuated ZnR activity in a neuronal cell line. Importantly, we observed widespread GPR39 labeling in CA3 neurons, suggesting a role for this receptor in mediating ZnR signaling in the hippocampus. Our results describe a unique role for synaptic Zn2+ acting as the physiological ligand of a metabotropic receptor and provide a novel pathway by which synaptic-Zn2+ can regulate neuronal function.

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Changes in extracellular zinc concentration participate in modulating fundamental cellular processes such as proliferation, secretion, and ion transport in a mechanism that is not well understood. Here, we show that a micromolar concentration of extracellular zinc triggers a massive release of calcium from thapsigarginsensitive intracellular pools in the colonocytic cell line HT29. Calcium release was blocked by a phospholipase-C inhibitor, indicating that formation of inositol 1,4,5-triphosphate is required for zinc-dependent calcium release. Zinc influx was not observed, indicating that extracellular zinc triggered the release. The Ca i 2؉ release was zinc specific and could not be triggered by other heavy metals. Furthermore, zinc failed to activate the Ca 2؉ -sensing receptor heterologously expressed in HEK293 cells. The zinc-induced Ca i 2؉ rise stimulated the activity of the Na ؉ ͞H ؉ exchanger in HT29 cells. Our results indicate that a previously uncharacterized extracellular, G protein-coupled, Zn 2؉ -sensing receptor is functional in colonocytes. Because Ca i 2؉ rise is known to regulate key cellular and signal-transduction processes, the zinc-sensing receptor may provide the missing link between extracellular zinc concentration changes and the regulation of cellular processes.Z inc is an essential micronutrient involved in structural and regulatory cellular functions. Zinc interacts with zinc-finger domains and acts as a cofactor of numerous enzymes (1, 2). Zinc ions also specifically bind to many membrane receptors, transporters, and channels, thereby modulating their activity (3). Therefore, it is not surprising that zinc deficiency affects multiple organs, including the digestive (4), immune (5), and neuronal (2) systems. A severe lack of zinc also is linked to the attenuation of growth and sexual development (2). Conversely, an excess of extracellular zinc is considered toxic. Indeed, brain ischemia is accompanied by a massive release of synaptic zinc permeating into neurons, leading to neuronal cell death (6-8). Furthermore, striking changes in plasma-zinc concentration occur during diverse pathophysiological syndromes including myocardial infarction, hepatic renal failure, and neoplastic processes (9). Despite the large fluctuations in extracellular zinc concentrations and their subsequent clinical importance, little is known about cellular signaling mechanisms that sense changes in extracellular-zinc concentration.The calcium-sensing receptor serves as an example for the importance of an ion-sensing mechanism. It is a G proteincoupled receptor that senses changes in extracellular calcium and regulates diverse cellular functions (10, 11). Although the existence of other ion-sensing mechanisms have been suggested (12), none have been characterized fully yet.Gastrointestinal pathology, manifested in severe diarrhea, is an important hallmark of zinc deficiency. Indeed, zinc has a major role in the duration and severity of diarrheal diseases (4). The morbidity and mortality caused by diarrheal diseas...