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TOXICOLOGY

Methylmercury Induces a Spontaneous, Transient Slow Inward Chloride Current in Purkinje Cells of Rat Cerebellar Slices

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

Methylmercury (MeHg; 10–100 µM) induced a spontaneous, transient, slow inward current in Purkinje cells in rat cerebellar slices. Insensitivity of this current to tetrodotoxin suggests that its generation is not related to presynaptic firing. The present study was designed to attempt to identify the ionic origin of this current. Neither Gd³⁺, a nonspecific cation channel blocker, nor tetrakis(2-pyridylmethyl)ethylethylenediamine, which chelates Zn²⁺, could prevent this current. Following dialysis of cells with a low-[Cl^–] pipette solution, the giant currents were inducible only when the cells were held at potentials more positive than 0 mV but not at potentials more negative than –60 mV. In addition, no giant currents were observed when cells were held at 0 mV under symmetrical [Cl^–] conditions. Thus, this current seems to be mediated by Cl^–. However, it was insensitive to the glycine receptor antagonist strychnine. The anion channel blockers 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) or niflumic acid suppressed GABA_A receptor-mediated spontaneous inhibitory postsynaptic currents. Niflumic acid also prevented appearance of this giant current; DIDS was only effective at more positive membrane potentials. Thus, this current seems to be carried by a voltage-dependent Cl^– channel. Reducing extracellular Ca²⁺ concentration and/or intracellular application of the Ca²⁺ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid seemed to be ineffective at preventing appearance of this current. Thus, these data do not seem to support the conclusion that this current is mediated by a Ca²⁺-activated Cl^– channel. The role that this current plays in MeHg-induced neurotoxicity is unknown.

Address correspondence to: Dr. William D. Atchison, Department of Pharmacology and Toxicology, B331 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317. E-mail: atchiso1{at}msu.edu

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