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 alpha 3 beta 2, alpha 3 beta 4 and alpha 4 beta 2 neuronal nicotinic acetylcholine receptor subunit combinations. In oocytes expressing the alpha 3 beta 2 subunit combination Pb2+ enhances the peak amplitude of nicotinic acetylcholine receptor-mediated inward currents evoked by superfusion with 100 microM acetylcholine. At concentrations of 1-250 microM, Pb2+ potentiates alpha 3 beta 2 receptor-mediated inward current concentration dependently by a factor of 1.1-11.0. Inward currents evoked by low (3 microM) and high (1 mM) concentrations of acetylcholine are potentiated to a similar extent. Conversely, in oocytes expressing the alpha 3 beta 4 subunit combination Pb2+ inhibits the nicotinic receptor-mediated inward currents evoked with 100 microM acetylcholine. Inhibitory effects are observed in the concentration range of 1 nM-100 microM Pb2+ but the degree of inhibition varies between oocytes. A similar inhibition of the alpha 4 beta 2 nicotinic receptor-mediated inward current by Pb2+ indicates that alpha as well as beta subunits are involved in the potentiating 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 and are discussed. The divalent cations Ca2+ and Mg2+ potentiate both alpha 3 beta 2 and alpha 3 beta 4 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 alpha and beta subunits of neuronal nicotinic acetylcholine receptors.
Zwart
R
R
Research Institute of Toxicology, Utrecht University, Netherlands.
Van Kleef
R G
RG
Milikan
J M
JM
Oortgiesen
M
M
Vijverberg
H P
HP
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism; D007854:Lead / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D009435:Synaptic Transmission; D014162:Transfection; D014982:Xenopus laevis
D007473:Ion Channels; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D007854:Lead; D008274:Magnesium; D002118:Calcium