Ca2+-sensitive inhibition by Pb2+ of α7-containing nicotinic acetylcholine receptors in hippocampal neurons

In the present study the patch-cramp technique was applied to cultured hippocampal neurons to determine the kinetics as well as the agonist concentration- and Ca2+-dependence of Pb2+-induced inhibition of alpha 7 nicotinic receptors (nAChRs). Evidence is provided that more than two-thirds of the inhibition by Pb2+ (3-30 mu M) of alpha 7 nAChR-mediated whole-cell currents (referred to as type IA currents) develops rapidly and is fully reversible upon washing. The estimated values for tau(onset) and tau(recovery) were 165 and 240 ms, respectively. The magnitude of the effect of Pb2+ was the same regardless of whether acetylcholine or choline was the agonist. Pre-exposure of the neurons for 800 ms to Pb2+ (30 mu M) decreased the amplitude and accelerated the decay phase of currents evoked by moderate to high agonist concentrations. In contrast, only the amplitude of currents evoked by low agonist concentrations was reduced when the neurons were exposed simultaneously to Pb2+ and the agonists. Taken together with the findings that Pb2+ reduces the frequency of opening and the mean open rime of alpha 7 nAChR channels, these data suggest that Pb2+ accelerates the rate of receptor desensitization. An additional reduction of type LA current amplitudes occurred after 2-min exposure of the neurons to Pb2+. This effect was not reversible upon washing of the neurons and was most Likely due to an intracellular action of Pb2+. Pb2+-induced inhibition of alpha 7 nAChRs, which was hindered by the enhancement of extracellular Ca2+ concentrations, may contribute to the neurotoxicity of the heavy metal. (C) 2000 Elsevier Science B.V. All rights reserved.