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TOXICOLOGY

Comparative Effects of Methylmercury and Hg²⁺ on Human Neuronal N- and R-Type High-Voltage Activated Calcium Channels Transiently Expressed in Human Embryonic Kidney 293 Cells

Department of Pharmacology and Toxicology, Institute of Environmental Toxicology and Neuroscience Program, Michigan State University, East Lansing, Michigan

Expression cDNA clones of _1B-1 or _1E-3 subunits coding for human neuronal N-(Ca_v2.2) or R-subtype (Ca_v2.3) Ca²⁺ channels, respectively, was combined with _2-b and _3-a Ca²⁺ channel subunits, and transfected into human embryonic kidney cells for transient expression to determine whether specific types of neuronal voltage-sensitive Ca²⁺ channels are affected differentially by methylmercury (MeHg) and Hg²⁺. For both Ca²⁺ channel subtypes, MeHg (0.125-5.0 µM) or Hg²⁺ (0.1-5 µM) caused a time- and concentration-dependent reduction of current. MeHg caused an initial, rapid component and a subsequent more gradual component of inhibition. The rapid component of block was completed between 100 and 150 s after beginning treatment. At 0.125 to 1.25 µM, MeHg caused a more gradual decline in current. Apparent IC₅₀ values were 1.3 and 1.1 µM for MeHg, and 2.2 and 0.7 µM for Hg²⁺ on N- and R-types, respectively. For N-type current, effects of Hg²⁺ were initially greater on the peak current than on the sustained current remaining at the end of a test pulse; subsequently, Hg²⁺ blocked both components of current. For R-type current, Hg²⁺ affected peak and sustained current approximately equally. Kinetics of inactivation also seemed to be affected by Hg²⁺ in cells expressing N-type but not R-type current. Washing with MeHg-free solution could not reverse effects of MeHg on either type of current. The effect of Hg²⁺ on N- but not R-type current was partially reversed by Hg²⁺-free wash solution. Therefore, different types of Ca²⁺ channels have differential susceptibility to neurotoxic mercurials even when expressed in the same cell type.

Address correspondence to: Dr. Bill Atchison, Department of Pharmacology and Toxicology, Michigan State University, B-331 Life Sciences Bldg., East Lansing, MI 48824-1317. E-mail: atchiso1{at}msu.edu

This article has been cited by other articles:

				B. Tarabova, M. Kurejova, Z. Sulova, M. Drabova, and L. Lacinova Inorganic Mercury and Methylmercury Inhibit the Cav3.1 Channel Expressed in Human Embryonic Kidney 293 Cells by Different Mechanisms J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 418 - 427. [Abstract] [Full Text] [PDF]