The experiments proposed will examine the expression, distribution, and glycosylation of neuronal nicotinic acetylcholine receptors and glutamate receptors in the mammalian nervous system. Transfection of cDNAs encoding glutamate receptors into cultured cells will be used to explore the relationship between receptor subunit composition and the sensitivity of the cell to kainic acid induced excitotoxicity. The working hypothesis is that neurodegenerative disease that are often associated with diseases of aging such as senile dementia can result from the altered subunit expression, receptor assembly, or subneuronal localization of glutamate or nicotinic acetylcholine receptors. The consequence of expressing receptors that are functionally altered or that are not within their normal context of expression could render neurons essentially nonfunctional, or susceptible to damage and possibly death. To begin the test of this hypothesis, antisera to subunits that compose these receptors have been prepared and will be used to localize these subunits, determine the associations between the subunits, and measure the glycosylation of each subunit in the brains of rats. Upon determining the association between glutamate receptor subunits and their location in vivo, the corresponding cDNAs will be transfected into cultured cells, and the influence that receptors of various subunit composition has on imparting to the transfected cell sensitivity to agonist induced excitotoxic death will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29NS030990-01
Application #
3478594
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-07-01
Project End
1993-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Twyman, R E; Rogers, S W; Gahring, L C et al. (1999) Antibodies to glutamate receptors: a role in excitatory dysregulation of the central nervous system? Adv Neurol 79:535-41
Gahring, L C; Rogers, S W; Twyman, R E (1997) Autoantibodies to glutamate receptor subunit GluR2 in nonfamilial olivopontocerebellar degeneration. Neurology 48:494-500
Gahring, L C; Cauley, K; Rogers, S W (1996) Kainic acid induced excitotoxicity and cfos expression in fibroblasts transfected with glutamate receptor subunit, GluR1. J Neurobiol 31:56-66
Cauley, K; Marks, M; Gahring, L C et al. (1996) Nicotinic receptor subunits alpha 3, alpha 4, and beta 2 and high affinity nicotine binding sites are expressed by P19 embryonal cells. J Neurobiol 30:303-14
Gahring, L C; Carlson, N G; Kulmar, R A et al. (1996) Neuronal expression of tumor necrosis factor alpha in the murine brain. Neuroimmunomodulation 3:289-303
Flores, C M; DeCamp, R M; Kilo, S et al. (1996) Neuronal nicotinic receptor expression in sensory neurons of the rat trigeminal ganglion: demonstration of alpha3beta4, a novel subtype in the mammalian nervous system. J Neurosci 16:7892-901
Twyman, R E; Gahring, L C; Spiess, J et al. (1995) Glutamate receptor antibodies activate a subset of receptors and reveal an agonist binding site. Neuron 14:755-62
Gahring, L C; Twyman, R E; Greenlee, J E et al. (1995) Autoantibodies to neuronal glutamate receptors in patients with paraneoplastic neurodegenerative syndrome enhance receptor activation. Mol Med 1:245-53
Rogers, S W; Andrews, P I; Gahring, L C et al. (1994) Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265:648-51
Britto, L R; Rogers, S W; Hamassaki-Britto, D E et al. (1994) Nicotinic acetylcholine receptors in the ground squirrel retina: localization of the beta 4 subunit by immunohistochemistry and in situ hybridization. Vis Neurosci 11:569-77

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