title: Perturbation of voltage-sensitive Ca2+ channel function by volatile organic solvents.
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.
authors.affiliation: Neurotoxicology Division, MD-B105-05, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. shafer.tim@epa.gov
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bushnell
authors.forename: Vernon A
authors.initials: VA
authors.lastname: Benignus
authors.forename: John J
authors.initials: JJ
authors.lastname: Woodward
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002138:Calibration; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008564:Membrane Potentials; D009474:Neurons / Q000187:drug effects; D009930:Organic Chemicals / Q000737:chemistry / Q000633:toxicity*; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D051381:Rats; D012015:Reference Standards; D012997:Solvents / Q000737:chemistry / Q000145:classification / Q000633:toxicity; D013750:Tetrachloroethylene / Q000032:analysis / Q000633:toxicity*; D014050:Toluene / Q000032:analysis / Q000633:toxicity*; D014241:Trichloroethylene / Q000032:analysis / Q000633:toxicity*; D014835:Volatilization
chemical_list: D015220:Calcium Channels; D009930:Organic Chemicals; D012997:Solvents; D014241:Trichloroethylene; D014050:Toluene; D013750:Tetrachloroethylene