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NEUROPHARMACOLOGY

Perturbation of Voltage-Sensitive Ca²⁺ Channel Function by Volatile Organic Solvents

Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (T.J.S., P.J.B., V.A.B.); and Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (J.J.W.)

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 (I_Ca) in nerve growth factor-differentiated pheochromocytoma (PC12) cells. All three VOCs affected I_Ca in a reversible, concentration-dependent manner. At +10-mV test potentials, VOCs inhibited I_Ca, whereas at test potentials of –20 and –10 mV, they potentiated it. The order of potency for inhibition (IC₅₀) was PERC (270 µM) > TOL (720 µM) > TCE (1525 µM). VOCs also changed I_Ca inactivation kinetics from a single- to double-exponential function. Voltage-ramp experiments suggested that VOCs shifted I_Ca activation in a hyperpolarizing direction; this was confirmed by calculating the half-maximal voltage of activation (V_{1/2, 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 (V_{1/2, inact}) from approximately –16 mV in control to –32, –35, and –20 mV in the presence of TOL, TCE, and PERC, respectively. Inhibition of I_Ca by TOL was confirmed in primary cultures of cortical neurons, where 827 µM 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.

Address correspondence to: Dr. Timothy J. Shafer, Neurotoxicology Division, MD-B105-05, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. E-mail: shafer.tim{at}epa.gov

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