Increasing evidence suggest that intracellular calcium mediator proteins may be critical targets for the toxic actions of Pb2+ ions. Recent studies in this laboratory demonstrated that in toxicologically relevant release of transmitters from presynaptic nerve terminals and catecholamines from adrenal chromaffin cells. It is hypothesized that Pb2+ triggers secretion by directly interacting with the putative Ca-trigger receptor of the secretory exocytosis. In this project, isolated bovine chromaffin cells will be used a model system in further studies of the mechanism and molecular target(s) of lead's action(s) as secretagogue. (1) Entry and metabolism of Pb2+ in intact cells will be studied using a combination of fluorescence and atomic absorption spectroscopy, in order to elucidate in detail the relationship between intracellular Pb2+ accumulation and its effect on the basal and stimulus evoked secretory responses of chromaffin cells; (2) Permeabilized chromaffin cells will be employed to characterize the pharmacology and ionic selectivity of the process of Pb2+ induced secretion; (3) Attempts will be made to identify the molecular target(s) of Pb2+ action in secretion. The extraordinary sensitivity of the secretory process to pM concentrations of Pb2+ suggest that transmitter release and hormone secretion could be affected in low level lead exposure. Elucidation of the interactions between Pb2+ and secretory cell functions should advance our understanding on the cellular and molecular level of deleterious health effects of low level lead exposure. In addition, this research may provide useful insights into the fundamental mechanisms underlying the secretory process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES004090-04A1
Application #
3251995
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1991-07-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Suszkiw, Janusz B (2004) Presynaptic disruption of transmitter release by lead. Neurotoxicology 25:599-604
Sun, X; Tian, X; Tomsig, J L et al. (1999) Analysis of differential effects of Pb2+ on protein kinase C isozymes. Toxicol Appl Pharmacol 156:40-5
Tomsig, J L; Suszkiw, J B (1996) Metal selectivity of exocytosis in alpha-toxin-permeabilized bovine chromaffin cells. J Neurochem 66:644-50
Sun, L R; Suszkiw, J B (1995) Extracellular inhibition and intracellular enhancement of Ca2+ currents by Pb2+ in bovine adrenal chromaffin cells. J Neurophysiol 74:574-81
Tomsig, J L; Suszkiw, J B (1995) Multisite interactions between Pb2+ and protein kinase C and its role in norepinephrine release from bovine adrenal chromaffin cells. J Neurochem 64:2667-73
Sun, L R; Suszkiw, J B (1994) Pb2+ activates potassium currents in bovine adrenal chromaffin cells. Neurosci Lett 182:41-3
Tomsig, J L; Suszkiw, J B (1993) Intracellular mechanism of Pb(2+)-induced norepinephrine release from bovine chromaffin cells. Am J Physiol 265:C1630-6
Shao, Z; Suszkiw, J B (1991) Ca2(+)-surrogate action of Pb2+ on acetylcholine release from rat brain synaptosomes. J Neurochem 56:568-74
Tomsig, J L; Suszkiw, J B (1991) Permeation of Pb2+ through calcium channels: fura-2 measurements of voltage- and dihydropyridine-sensitive Pb2+ entry in isolated bovine chromaffin cells. Biochim Biophys Acta 1069:197-200
Tomsig, J L; Suszkiw, J B (1990) Pb2(+)-induced secretion from bovine chromaffin cells: fura-2 as a probe for Pb2+. Am J Physiol 259:C762-8

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