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Perturbation of voltage-sensitive Ca2+ channel function by volatile organic solvents
Timothy J Shafer1, Philip J Bushnell, Vernon A Benignus
1Neurotoxicology Division, MD-B105-05, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. shafer.tim@epa.gov
The Journal of Pharmacology and Experimental Therapeutics
|August 20, 2005
Summary
Volatile organic compounds (VOCs) like toluene, TCE, and PERC disrupt neuronal calcium channels, affecting their function. This perturbation of voltage-sensitive calcium channels may explain the acute neurotoxic effects of these common environmental chemicals.
Area of Science:
- Neuroscience
- Environmental Health
- Toxicology
Background:
- The precise mechanisms behind the acute neurophysiological and behavioral impacts of volatile organic compounds (VOCs) are not fully understood.
- However, it is known that VOCs can interfere with the normal functioning of neuronal ion channels.
Purpose of the Study:
- To investigate the effects of toluene (TOL), trichloroethylene (TCE), and perchloroethylene (PERC) on whole-cell calcium currents (ICa).
- To explore how these VOCs impact the kinetics and voltage-dependence of calcium channel activity in neurons.
Main Methods:
- Whole-cell patch-clamp electrophysiology was used to record calcium currents (ICa) in nerve growth factor-differentiated PC12 cells.
- Voltage-ramp experiments and Boltzmann equation analysis were employed to assess changes in ICa activation and inactivation kinetics.
- Toluene's effects were also validated in primary cultures of cortical neurons.
Main Results:
- Toluene, TCE, and PERC reversibly altered ICa in a concentration-dependent manner.
- VOCs inhibited ICa at +10 mV but potentiated it at -20 and -10 mV, with varying potencies (PERC > TOL > TCE for inhibition).
- VOCs shifted the voltage-dependence of ICa activation and inactivation, and altered inactivation kinetics, with toluene confirmed to inhibit currents in primary cortical neurons.
Conclusions:
- Volatile organic compounds significantly perturb the function of voltage-sensitive calcium channels in neurons.
- These disruptions in calcium channel activity represent a potential mechanism contributing to the acute neurotoxicity observed with VOC exposure.