The neuropathological outcome associated with abnormal activation of glutamate receptors specific for N-methyl-D-aspartate (NMDA) has been implicated in stroke and in a variety of neurodegenerative disorders. The modulation of NMDA receptor-mediated function by endogenous factors may have profound implications in the outcome of glutamate neurotoxicity. Experiments outlined in this proposal are aimed at evaluating the role of a novel modulatory site on the NMDA receptor which is sensitive to sulfhydryl redox reagents. Since the injurious sequelae accompanying cerebral ischemia/reperfusion injury involve changes in redox equivalents, including the generation of oxygen free radicals, this modulatory site on the NMDA receptor may be intimately involved with the outcome of stroke.
The specific aims of these studies are: (1) to establish the actions of oxygen free radicals on the redox modulatory site of the NMDA receptor, (2)to study the effects of the essential nutrient pyrroloquinoline quinone (PQQ) on the redox modulatory site of the NMDA receptor, (3)to study the action of """"""""reactive"""""""" disulfide compounds on the NMDA receptor, and (4) to examine the kinetic changes in NMDA receptor function following chemical modifications with sulfhydryl redox reagents. The experiments outlined in this proposal utilized a well-defined culture system of rat cerebral cortex. Electrophysiological studies utilizing patch-clamp technology will be combined with intracellular calcium determinations, radioactive ligand binding, and neurotoxicity assays to achieve the proposed aims. The studies planned here will provide a more accurate picture of the events accompanying ischemia/reperfusion injury in the central nervous system, especially as they pertain to NMDA receptor function. Investigations aimed at these processes could lead to better prevention programs as well as to improved treatments for stroke. In addition, these studies may lead to the discovery of probes that may specifically label the NMDA receptor and aid in its biochemical characterization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029365-04
Application #
2267552
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1991-04-01
Project End
1995-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Physiology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lee, Hanmi; Chen, Carol Xiu-Qing; Liu, Yong-Jian et al. (2005) KCC2 expression in immature rat cortical neurons is sufficient to switch the polarity of GABA responses. Eur J Neurosci 21:2593-9
Herin, Greta Ann; Aizenman, Elias (2004) Amino terminal domain regulation of NMDA receptor function. Eur J Pharmacol 500:101-11
McLaughlin, BethAnn; Hartnett, Karen A; Erhardt, Joseph A et al. (2003) Caspase 3 activation is essential for neuroprotection in preconditioning. Proc Natl Acad Sci U S A 100:715-20
Leszkiewicz, Daniel N; Aizenman, Elias (2003) Reversible modulation of GABA(A) receptor-mediated currents by light is dependent on the redox state of the receptor. Eur J Neurosci 17:2077-83
Leszkiewicz, Daniel N; McLaughlin, Beth Ann; Aizenman, Elias (2002) Protein kinases and light: unlikely partners in a receptor localization puzzle. Physiol Behav 77:533-6
Du, Shen; McLaughlin, BethAnn; Pal, Sumon et al. (2002) In vitro neurotoxicity of methylisothiazolinone, a commonly used industrial and household biocide, proceeds via a zinc and extracellular signal-regulated kinase mitogen-activated protein kinase-dependent pathway. J Neurosci 22:7408-16
Leszkiewicz, Daniel; Aizenman, Elias (2002) A role for the redox site in the modulation of the NMDA receptor by light. J Physiol 545:435-40
Santos, S; Aizenman, E (2002) Functional expression of muscle-type nicotinic acetylcholine receptors in rat forebrain neurons in vitro. Methods Find Exp Clin Pharmacol 24:63-6
McLaughlin, B; Pal, S; Tran, M P et al. (2001) p38 activation is required upstream of potassium current enhancement and caspase cleavage in thiol oxidant-induced neuronal apoptosis. J Neurosci 21:3303-11
Herin, G A; Du, S; Aizenman, E (2001) The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site. J Neurochem 78:1307-14

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