Potentiation and inhibition of subtypes of neuronal nicotinic acetylcholine receptors by Pb2+

Effects of inorganic lead (Pb²⁺) on defined subtypes of neuronal nicotinic acetylcholine receptors have been investigated. Voltage clamp experiments have been performed on Xenopus oocytes expressing α3β2, α3β4 and α4β2 neuronal nicotinic acetylcholine receptor subunit combinations. In oocytes expressing the α3β2 subunit combination Pb²⁺ enhances the peak amplitude of nicotinic acetylcholine receptor-mediated inward currents evoked by superfusion with 100 μM acetylcholine. At concentrations of 1–250 μM, Pb²⁺ potentiates α3β2 receptor-mediated inward current concentration dependently by a factor of 1.1–11.0. Inward currents evoked by low (3 μM) and high (1 mM) concentrations of acetylcholine are potentiated to a similar extent. Conversely, in oocytes expressing the α3β4 subunit combination Pb²⁺ inhibits the nicotinic receptor-mediated inward currents evoked with μM acetylcholine. Inhibitory effects are observed in the concentration range of 1 nM–100 μM Pb²⁺, but the degree of inhibition varies between oocytes. A similar inhibition of the α4β2 nicotinic receptor-mediated inward current by Pb²⁺ indicates that α as well as β subunits are involved in the potentiating and inhibitory effects. Possible reasons for the variation in the inhibitory effects of Pb²⁺ on α3β4 and α4β4 nicotinic receptor-mediated inward currents have been investigated and are discussed. The divalent cations Ca²⁺ and Mg²⁺ potentiate both α3β2 and α3β4 nicotinic receptor-mediated inward currents. The distinct modulation of receptor function by Pb²⁺ and by Ca²⁺ and Mg²⁺ and the dependence of the modulatory effect of Pb²⁺ on subunit composition suggest that Pb²⁺ interacts with multiple sites on the α and β subunits of neuronal nicotinic acetylcholine receptors.