The underlying mechanism(s) of neurological disorders caused by lead (Pb2+) have been correlated to the disruption of functioning of a number of neurotransmitter systems leading to impairment of neural transmission. However, the relationship between cognitive dysfunction and Pb2+ exposure is still unclear. Pb2+ exposure alters Ca2+ homeostasis which plays a critical role in neuronal development and plasticity. Recent evidence suggests that (1) nitric oxide synthase (NOS) activity plays a pivotal role in synaptic plasticity, and (2) nitric oxide (NO)-mediated carbon monoxide (CO) and cGMP generation and cGMP-dependent protein kinase (PKG) activity can alter Ca2+ homeostasis via cyclic ADP ribose (cADPR)- and inositol 1,4,5-triphosphate (InsP3)-gated Ca2+ channels. Pb2+, in vitro, decreases NOS activity of brain, and it is likely that Pb(2+)- induced decrease in NOS activity and NO levels leads to changes in NO-mediated CO generation by heme oxygenase (HO-2), cGMP generation by soluble guanylate cyclase (sGC), and mobilization of intracellular Ca2+. The hypothesis to be tested is that Pb2+ exposure decreases NOS activity and NO levels resulting in the modulation of NO-mediated signal transduction via CO and cGMP, and Ca2+ homeostasis, which play a crucial role during the development of the central nervous system, leading to cognitive dysfunction. To test the above hypothesis, the present study is proposed to assess the effect of Pb2+ exposure on: (1) NOS and HO-2 activity, (2) sGC activity, a target for NO and CO, (3) cGMP levels, (4) dGMP-dependent protein kinase (PKG) activity, (5) cADPR and InsP3 levels, and (6) cADPR- and InsP3-dependent Ca2+ release and their modulation by PKG- mediated phosphorylation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21GM060853-02
Application #
6182158
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Toliver, Adolphus
Project Start
1999-05-01
Project End
2002-08-31
Budget Start
2000-05-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$137,325
Indirect Cost
Name
Savannah State University
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
879931509
City
Savannah
State
GA
Country
United States
Zip Code
31404
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Chetty, Chellu S; Vemuri, Mohan C; Campbell, Khamisi et al. (2005) Lead-induced cell death of human neuroblastoma cells involves GSH deprivation. Cell Mol Biol Lett 10:413-23
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Chetty, C S; Reddy, G R; Murthy, K S et al. (2001) Perinatal lead exposure alters the expression of neuronal nitric oxide synthase in rat brain. Int J Toxicol 20:113-20