It is widely appreciated that glutamate-triggered acute neuronal injury is dependent on calcium entry into neurons and that the most rapid form of injury is mediated by the activation of N-methyl-D-aspartate receptors. However, in previous studies that have used in vitro models of neuronal injury it has been difficult to account for the specificity of the neurotoxic effects of NMDA receptor activation because of the difficulty in distinguishing toxic and non-toxic intracellular calcium changes. In re-evaluating the studies that link calcium changes to neuronal injury it becomes apparent that it is necessary to reconsider the issues of the magnitude of calcium changes that are associated with injury because previous studies may not have provided accurate results. In addition, unappreciated issues of the selectivity of the commonly used fluorescent dyes for intracellular divalent cations suggest that magnesium and zinc should also be considered as candidate neurotoxins in excitotoxic injury. The long-term goal of these studies is to understand the ionic mechanisms by which glutamate kills neurons. The applicants plan to: determine if non-NMDA receptor agonists induce acute neuronal injury if the magnitude of the calcium change they induce is increased; determine if the magnitude of the intracellular Mg change in neurons is stimulated by glutamate, and how would this alter mitochondrial function; determine the magnitude of intracellular zinc changes and how they may relate to neuronal injury; and, to determine the mechanisms neurons are protected from zinc-mediated injury. There are a number of potentially important interrelationships between the various cation-mediated forms of injury, and the proposed approach is to investigate these relationships, and, also to exploit the similarities in methodology that can be adapted to measure each ion of interest.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034138-06
Application #
6187873
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (03))
Program Officer
Chiu, Arlene Y
Project Start
1995-05-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
6
Fiscal Year
2000
Total Cost
$244,907
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Devinney, Michael J; Malaiyandi, Latha M; Vergun, Olga et al. (2009) A comparison of Zn2+- and Ca2+-triggered depolarization of liver mitochondria reveals no evidence of Zn2+-induced permeability transition. Cell Calcium 45:447-55
Dineley, Kirk E; Devinney 2nd, Michael J; Zeak, Jennifer A et al. (2008) Glutamate mobilizes [Zn2+] through Ca2+ -dependent reactive oxygen species accumulation. J Neurochem 106:2184-93
Malaiyandi, Latha M; Vergun, Olga; Dineley, Kirk E et al. (2005) Direct visualization of mitochondrial zinc accumulation reveals uniporter-dependent and -independent transport mechanisms. J Neurochem 93:1242-50
Malaiyandi, Latha M; Honick, Anthony S; Rintoul, Gordon L et al. (2005) Zn2+ inhibits mitochondrial movement in neurons by phosphatidylinositol 3-kinase activation. J Neurosci 25:9507-14
Devinney 2nd, Michael J; Reynolds, Ian J; Dineley, Kirk E (2005) Simultaneous detection of intracellular free calcium and zinc using fura-2FF and FluoZin-3. Cell Calcium 37:225-32
Dineley, Kirk E; Richards, Lauren L; Votyakova, Tatyana V et al. (2005) Zinc causes loss of membrane potential and elevates reactive oxygen species in rat brain mitochondria. Mitochondrion 5:55-65
Malaiyandi, Latha M; Dineley, Kirk E; Reynolds, Ian J (2004) Divergent consequences arise from metallothionein overexpression in astrocytes: zinc buffering and oxidant-induced zinc release. Glia 45:346-53
Dineley, Kirk E; Votyakova, Tatyana V; Reynolds, Ian J (2003) Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J Neurochem 85:563-70
Dineley, K E; Brocard, J B; Reynolds, I J (2002) Elevated intracellular zinc and altered proton homeostasis in forebrain neurons. Neuroscience 114:439-49
Kress, Geraldine J; Dineley, Kirk E; Reynolds, Ian J (2002) The relationship between intracellular free iron and cell injury in cultured neurons, astrocytes, and oligodendrocytes. J Neurosci 22:5848-55

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