Infusion of the biological sciences with genetic sequencing of entire genomes has sped discovery, but complete utilization of this information awaits detailed information about gene regulation. Nowhere is this more apparent than in the nervous system, where environmental interactions with genetic information take the form of learning and memory. Glutamate is a paramount neurotransmitter in these processes, but also becomes a neurotoxin in several neurodegenerative conditions. Published literature suggests that activation of glutamate receptors can induce the transcription factor NF-kappa-B in CNS neurons; glutamatergic input has also been implicated in an apparent constitutive basal activity of NF-kappa-B in these cells. However, more stringent tests performed in support of this proposal indicate that glutamate does not activate NF-kappa-B DNA-binding in neurons cultured from the cerebral cortex. Furthermore, the only factors constitutively binding NF-kappa-B target sites are Sp1 and related proteins, and glutamate decreases this activity. Together, these results indicate that NF-kappa-B is not a glutamate-responsive transcription factor as previously thought. But considerable evidence still suggests that kappa-B elements control genes important for neuronal viability. The following hypothesis will be tested: Sp1-related proteins influence survival-promoting genes through binding to kappa-B elements, and glutamate toxicity involves a reduced binding of kappa-B elements by both Sp1 and NF-kappa-B. First, glutamate-evoked events that squelch NF-kappa-B activity in cortical neurons will be elucidated through tests of post-translational modifications and interactions with other proteins. Second, the role of NF-kappa-B in protection of neurons against glutamate toxicity will be examined. Third, mechanisms by which glutamate suppresses the activity of Sp1-related factors will be explored. Finally, the ability of Sp1-related proteins to control neuronal transcription through kappa-B cis elements, with particular regard to survival-promoting genes, will be explored. These studies should shed light on a contentious issue, namely, the role of NF-kappa-B and its DNA target sites in cerebral neurons. As such, this body of work could have direct impact on the mechanisms by which a major neurotransmitter impacts on the genetic correlates of memory, learning, and excitotoxic cell death, paradigms of considerable significance to human mental health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046439-04
Application #
7161716
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Mamounas, Laura
Project Start
2004-01-20
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$249,088
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Mao, Xianrong; Phanavanh, Bounleut; Hamdan, Hamdan et al. (2016) NF?B-inducing kinase inhibits NF?B activity specifically in neurons of the CNS. J Neurochem 137:154-63
Mao, Xianrong R; Moerman-Herzog, Andrea M; Chen, Yuzhi et al. (2009) Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factors. J Neuroinflammation 6:16
Mao, Xianrong; Yang, Shao-Hua; Simpkins, James W et al. (2007) Glutamate receptor activation evokes calpain-mediated degradation of Sp3 and Sp4, the prominent Sp-family transcription factors in neurons. J Neurochem 100:1300-14
Mao, Xianrong; Moerman-Herzog, Andrea M; Wang, Wei et al. (2006) Differential transcriptional control of the superoxide dismutase-2 kappaB element in neurons and astrocytes. J Biol Chem 281:35863-72
Massa, Paul T; Aleyasin, Hossein; Park, David S et al. (2006) NFkappaB in neurons? The uncertainty principle in neurobiology. J Neurochem 97:607-18
Wu, Sheng-Zhou; Jiang, Shujun; Sims, Terry J et al. (2005) Schwann cells exhibit excitotoxicity consistent with release of NMDA receptor agonists. J Neurosci Res 79:638-43
Barger, Steven W; Moerman, Andrea M; Mao, Xianrong (2005) Molecular mechanisms of cytokine-induced neuroprotection: NFkappaB and neuroplasticity. Curr Pharm Des 11:985-98
Liu, Ling; Li, Yuekui; Van Eldik, Linda J et al. (2005) S100B-induced microglial and neuronal IL-1 expression is mediated by cell type-specific transcription factors. J Neurochem 92:546-53
Wu, Shengzhou; Barger, Steven W (2004) Induction of serine racemase by inflammatory stimuli is dependent on AP-1. Ann N Y Acad Sci 1035:133-46
Barger, Steven W (2004) An unconventional hypothesis of oxidation in Alzheimer's disease: intersections with excitotoxicity. Front Biosci 9:3286-95

Showing the most recent 10 out of 11 publications