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PERTURBATION OF VOLTAGE-SENSITIVE CALCIUM FUNCTION IN PHEOCHROMOCYTOMA CELLS BY VOLATILE ORGANIC SOLVENTS.
Citation:
Shafer, T J., R. Tillar, AND J. J. Woodward. PERTURBATION OF VOLTAGE-SENSITIVE CALCIUM FUNCTION IN PHEOCHROMOCYTOMA CELLS BY VOLATILE ORGANIC SOLVENTS. Presented at Society of Toxicology, Nashville, TN, 3/17-21/2002.
Description:
Volatile organic solvents such as toluene (TOL) and trichloroethylene perturb nervous system function and share characteristic effects with other central nervous system depressants such as anesthetic gasses, ethanol, benzodiazepines and barbiturates. Recently, mechanistic studies have indicated that ion channels, including voltage-sensitive calcium channels (VSCC), are sites of action for CNS anesthetics. Thus, the hypothesis that TOL and trichloroethylene act on VSCC was tested by examining effects of these compounds on calcium current recorded utilizing whole-cell patch clamp techniques in pheochromocytoma (PC12) cells. Calcium currents were evoked by a 200 msec step depolarization from a holding potential of -70 to +20 mV. TOL rapidly and reversibly inhibited calcium current in undifferentiated as well as NGF-differentiated cells. In NGF-differentiated cells, TOL (0.3 - 5.0 mM) decreased calcium current in a concentration-dependent manner with an estimated IC50 of 1 mM. TOL (3 mM) decreased the amplitude of calcium current at the end of the 200 msec voltage step to a greater extent than the peak calcium current. In undifferentiated cells, peak and end currents in the presence of 3 mM TOL were 58.9 ? 5.7 and 31.9 ? 1.6 % of their respective control amplitudes, whereas in NGF-differentiated cells, peak and end currents were 31.0 ? 4.0 and 15.3 ? 3.1 % of control, respectively. When the current-voltage (I/V) relationship was examined, TOL reduced calcium current amplitude at test potentials between 0 and +40 mV, but increased current amplitude at test potentials of -20 and -10 mV. In both undifferentiated and NGF-differentiated PC12 cells, TOL inhibited KCl-induced increases in intracellular Ca2+ in a concentration-dependent manner; the potency of TOL was greater in NGF-differentiated cells. TOL was without effect on basal intracellular Ca2+ levels. Like TOL, trichloroethylene (5 mM) inhibited calcium currents in PC12 cells in a rapid and reversible manner. These results suggest that VSCC are sensitive to disruption by volatile organic solvents. (This abstract does not reflect EPA policy).