Ca(2+)-sensitive inhibition by Pb(2+) of alpha7-containing nicotinic acetylcholine receptors in hippocampal neurons.
In the present study the patch-clamp technique was applied to cultured hippocampal neurons to determine the kinetics as well as the agonist concentration- and Ca(2+)-dependence of Pb(2+)-induced inhibition of alpha7 nicotinic receptors (nAChRs). Evidence is provided that more than two-thirds of the inhibition by Pb(2+) (3-30 microM) of alpha7 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 Pb(2+) was the same regardless of whether acetylcholine or choline was the agonist. Pre-exposure of the neurons for 800 ms to Pb(2+) (30 microM) 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 Pb(2+) and the agonists. Taken together with the findings that Pb(2+) reduces the frequency of opening and the mean open time of alpha7 nAChR channels, these data suggest that Pb(2+) accelerates the rate of receptor desensitization. An additional reduction of type IA current amplitudes occurred after 2-min exposure of the neurons to Pb(2+). This effect was not reversible upon washing of the neurons and was most likely due to an intracellular action of Pb(2+). Pb(2+)-induced inhibition of alpha7 nAChRs, which was hindered by the enhancement of extracellular Ca(2+) concentrations, may contribute to the neurotoxicity of the heavy metal.
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA.
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Mike
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Pereira
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Albuquerque
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002478:Cells, Cultured; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007854:Lead / Q000494:pharmacology*; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism*; D009994:Osmolar Concentration; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D011978:Receptors, Nicotinic; D007854:Lead; D000109:Acetylcholine; D002118:Calcium