1. Extracellular and intracellular effects of aluminum (Al) on voltage-activated calcium channel currents (VACCCs) of cultured rat dorsal root ganglion (DRG) neurons were investigated. Al (0.54 to 5.4 micrograms/ml = 20-200 microM) applied extracellularly reduces VACCCs in a concentration-dependent manner. The IC50 was calculated to be 2.3 micrograms/ml (83 microM). All types of VACCCs were similarly reduced by Al treatment. A slight shift of the current-voltage relation to depolarized potentials was observed for higher Al concentrations (> 2 micrograms/ml). The action of Al was found to be use dependent, with little recovery (max. 20%) after wash. 2. The effect of Al was highly pH dependent in the investigated range (pH 6.4 to 7.8). We observed a rightward shift of the concentration-response curve at pH 7.7 (IC50:3.1 micrograms/ml) and a leftward shift at pH 6.4 (IC50:0.56 microgram/ml) compared to the concentration-response curve at pH 7.3. 3. The VACCC declined when 2.7 micrograms/ml Al was added to the internal solution. A steady state was reached within a few minutes. Additional extracellular application of the same concentration lead to an additional decrease of the current. These observations strongly suggest 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 additional internal binding site may contribute to its neurotoxicity.