POTENTIATION AND INHIBITION OF SUBTYPES OF NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS BY PB2+

Effects of inorganic lead (Pb2+) on defined subtypes of neuronal nicot inic acetylcholine receptors have been investigated. Voltage clamp exp eriments have been performed on Xenopus oocytes expressing alpha 3 bet a 2, alpha 3 beta 4 and alpha 4 beta 2 neuronal nicotinic acetylcholin e receptor subunit combinations. In oocytes expressing the alpha 3 bet a 2 subunit combination Pb2+ enhances the peak amplitude of nicotinic acetylcholine receptor-mediated inward currents evoked by superfusion with 100 mu M acetylcholine. At concentrations of 1-250 mu M, Pb2+ pot entiates alpha 3 beta 2 receptor-mediated inward current concentration dependently by a factor of 1.1-11.0. Inward currents evoked by low (3 mu M) and high (1 mM) concentrations of acetylcholine are potentiated to a similar extent. Conversely, in oocytes expressing the alpha 3 be ta 4 subunit combination Pb2+ inhibits the nicotinic receptor-mediated inward currents evoked with 100 mu M acetylcholine. Inhibitory effect s are observed in the concentration range of 1 nM-100 mu M Pb2+, but t he degree of inhibition varies between oocytes. A similar inhibition o f the alpha 4 beta 2 nicotinic receptor-mediated inward current by Pb2 + indicates that alpha as well as beta subunits are involved in the po tentiating and inhibitory effects. Possible reasons for the variation in the inhibitory effects of Pb2+ on alpha 3 beta 4 and alpha 4 beta 2 nicotinic receptor-mediated inward currents have been investigated an d are discussed. The divalent cations Ca2+ and Mg2+ potentiate both al pha 3 beta 2 and alpha 3 beta 4 nicotinic receptor-mediated inward cur rents. The distinct modulation of receptor function by pb(2+) and by C a2+ and Mg2+ and the dependence of the modulatory effect of Pb2+ on su bunit composition suggest that Pb2+ interacts with multiple sites on t he alpha and beta subunits of neuronal nicotinic acetylcholine recepto rs.