Ca2+-sensitive inhibition by Pb2+ of alpha 7-containing nicotinic acetylcholine receptors in hippocampal neurons

In the present study the patch-cramp technique was applied to cultured hipp ocampal neurons to determine the kinetics as well as the agonist concentrat ion- and Ca2+-dependence of Pb2+-induced inhibition of alpha 7 nicotinic re ceptors (nAChRs). Evidence is provided that more than two-thirds of the inh ibition 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 u pon 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-exposu re 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 a gonist concentrations was reduced when the neurons were exposed simultaneou sly to Pb2+ and the agonists. Taken together with the findings that Pb2+ re duces the frequency of opening and the mean open rime of alpha 7 nAChR chan nels, these data suggest that Pb2+ accelerates the rate of receptor desensi tization. An additional reduction of type LA current amplitudes occurred af ter 2-min exposure of the neurons to Pb2+. This effect was not reversible u pon washing of the neurons and was most Likely due to an intracellular acti on of Pb2+. Pb2+-induced inhibition of alpha 7 nAChRs, which was hindered b y the enhancement of extracellular Ca2+ concentrations, may contribute to t he neurotoxicity of the heavy metal. (C) 2000 Elsevier Science B.V. All rig hts reserved.