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J Pharmacol Exp Ther

Title:		Perturbation of voltage-sensitive Ca2+ channel function by volatile organic solvents
Author(s):		Shafer TJ; Bushnell PJ; Benignus VA; Woodward JJ;
Address:		"Neurotoxicology Division, MD-B105-05, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. shafer.tim@epa.gov"
Journal Title:		J Pharmacol Exp Ther
Year:		2005
Volume:		20050818
Issue:		3
Page Number:		1109 - 1118
DOI:		10.1124/jpet.105.090027
ISSN/ISBN:		0022-3565 (Print) 0022-3565 (Linking)
Abstract:		"The mechanisms underlying the acute neurophysiological and behavioral effects of volatile organic compounds (VOCs) remain to be elucidated. However, the function of neuronal ion channels is perturbed by VOCs. The present study examined effects of toluene (TOL), trichloroethylene (TCE), and perchloroethylene (PERC) on whole-cell calcium current (ICa) in nerve growth factor-differentiated pheochromocytoma (PC12) cells. All three VOCs affected ICa in a reversible, concentration-dependent manner. At +10-mV test potentials, VOCs inhibited ICa, whereas at test potentials of -20 and -10 mV, they potentiated it. The order of potency for inhibition (IC50) was PERC (270 microM) > TOL (720 microM) > TCE (1525 microM). VOCs also changed ICa inactivation kinetics from a single- to double-exponential function. Voltage-ramp experiments suggested that VOCs shifted ICa activation in a hyperpolarizing direction; this was confirmed by calculating the half-maximal voltage of activation (V1/2, act) in the absence and presence of VOCs using the Boltzman equation. V(1/2, act) was shifted from approximately -2 mV in control to -11, -12, and -16 mV by TOL, TCE, and PERC, respectively. Similarly, VOCs shifted the half-maximal voltage of steady-state inactivation (V1/2, inact) from approximately -16 mV in control to -32, -35, and -20 mV in the presence of TOL, TCE, and PERC, respectively. Inhibition of ICa by TOL was confirmed in primary cultures of cortical neurons, where 827 microM TOL inhibited current by 61%. These data demonstrate that VOCs perturb voltage-sensitive Ca2+ channel function in neurons, an effect that could contribute to the acute neurotoxicity of these compounds"
Keywords:		"Action Potentials/drug effects/physiology Animals Calcium Channels/*drug effects Calibration Cerebral Cortex/cytology Dose-Response Relationship, Drug Kinetics Membrane Potentials Neurons/drug effects Organic Chemicals/chemistry/*toxicity PC12 Cells Patch;"
Notes:		"MedlineShafer, Timothy J Bushnell, Philip J Benignus, Vernon A Woodward, John J eng R01 DA013951/DA/NIDA NIH HHS/ Comparative Study Research Support, U.S. Gov't, Non-P.H.S. 2005/08/20 J Pharmacol Exp Ther. 2005 Dec; 315(3):1109-18. doi: 10.1124/jpet.105.090027. Epub 2005 Aug 18"