Zinc ion homeostasis in cellular physiology and experimental models of traumatic brain injury

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Title: Zinc ion homeostasis in cellular physiology and experimental models of traumatic brain injury
Author: Yuan Li
Abstract: A major yet unsolved quest in treating traumatic brain injury (TBI ) is the understanding of the secondary cellular injury that contributes to cell death . Whether zinc ions are toxic or protective in TBI is controversial . As an essential human micronutrient , zinc is needed for the structure and function of at least 3 ,000 proteins , and thus affects almost any aspect of cellular function . Although extremely low , intracellular zinc ion concentrations , [Zn2+]i , are tightly controlled to ensure optimal physiology and to avoid toxicity . Furthermore , zinc ions are now believed to be signaling ions , especially in neuronal systems . This dissertation addresses the dynamics of [Zn2+]i and quantitatively defines its safe range in particular cell types . [Zn2+]i was measured to be pico - to nanomolar in undifferentiated and differentiated rat pheochromocytoma (PC12 ) cells and in rat glioma (C6 ) cells . When PC12 cells proliferate , [Zn2+]i undergoes precisely controlled fluctuations with two peaks within one cell cycle . These results demonstrate that the already established requirement for zinc in the cell cycle and in differentiation relates to the availability of zinc ions . In a mechanical model of cellular injury , namely rapid stretch injury (RSI ) , nitric oxide induces an increase in [Zn2+]i that subsequently may protect cells by repressing the generation of ROS . A peak at one hour was followed by decreased [Zn2+]i . In PC12 cells , [Zn2+]i dropped below its normal level , indicating that these cells were in a state of ¡°zinc ion deficiency¡± hours after RSI . In an in vivo model of neural injury , namely fluid percussion TBI of rats , changes of [Zn2+]i were indirectly demonstrated by measuring the levels and states of the zinc -binding protein , metallothionein /thionein , in the hippocampus and the cortex . These results demonstrate that [Zn2+]i as well as zinc buffering dynamically fluctuate to adapt to the requirements of cellular functions , even when [Zn2+]i is extremely low inside the cell . They suggest that toxicity occurs when [Zn2+]i falls outside the safety thresholds . Therefore , when , where , how much and in which form zinc is present determine whether chelation or supplementation is an option for treatment . These new concepts provide new leads for developing strategies to treat TBI .
URI: http : / /hdl .handle .net /2152 .3 /52
Date: 2009-03-06

Citation

Zinc ion homeostasis in cellular physiology and experimental models of traumatic brain injury. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /52 .

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