ACTIONS OF ALUMINUM ON VOLTAGE-ACTIVATED CALCIUM-CHANNEL CURRENTS

1. Extracellular and intracellular effects of aluminum (Al) on voltage -activated calcium channel currents (VACCCs) of cultured rat dorsal ro ot ganglion (DRG) neurons were investigated. Al (0.54 to 5.4 mu g/ml = 20-200 mu M) applied extracellularly reduces VACCCs in a concentratio n-dependent manner. The IC50 was calculated to be 2.3 mu g/ml (53 mu M ). Ah types of VACCCs were similarly reduced by Al treatment. A slight shift of the current-voltage relation to depolarized potentials was o bserved for higher Al concentrations (>2 mu g/ml). The action of Al wa s found to be use dependent, with little recovery (max. 20%) after was h. 2. The effect of Al was highly pH dependent in the investigated ran ge (pH 6.4 to 7.8). We observed a rightward shift of the concentration -response curve at pH 7.7 (IC50:3.1 mu g/ml) and a leftward shift at p H 6.4 (IC50:0.56 mu g/ml) compared to the concentration-response curve at pH 7.3. 3. The VACCC declined when 2.7 mu g/ml Al was added to the internal solution. A steady state was reached within a few minutes. A dditional extracellular application of the same concentration lead to an additional decrease of the current. These observations strongly sug gest the existence of both intracellular and extracellular accessible binding sites for Al on voltage-activated calcium channels (VACCs). 4. The special characteristics of the action of Al on VACCCs, i.e., the irreversibility, use dependence, and pH dependence, as well as the add itional internal binding site may contribute to its neurotoxicity.