title: Dual, non-competitive interaction of lead with neuronal nicotinic acetylcholine receptors in N1E-115 neuroblastoma cells.
abstract: In cultured mouse neuroblastoma N1E-115 cells, inorganic lead (Pb2+) affects inward currents induced by activation of neuronal type nicotinic acetylcholine receptors (nAChR) in a biphasic manner. At nanomolar concentrations a blocking action is observed, while at submillimolar concentrations this blocking effect is reversed, resulting in a U-shaped concentration-effect curve. Maximal block by 90% is observed at 1-3 microM Pb2+. The interactions of Pb2+ with nAChR were examined at the blocking concentration of 10 nM Pb2+ and at 10 microM Pb2+, presenting the reversal of block. The fitted Emax for nAChR receptor activation by ACh was attenuated at both high and low Pb2+ concentrations by 24% and 54%, respectively. The EC50 values of the activation curves were not significantly altered; amounting to 53 microM, 64 microM and 86 microM ACh in the control situation and in the presence of 10 nM and 10 microM Pb2+, respectively. Further, receptor desensitization and ion channel block by ACh were also not affected by Pb2+. The results indicate that Pb2+ affects nAChR in a dual manner that involves inhibition and potentiation, both by non-competitive interactions. Neuronal nAChR expressed in N1E-115 cells resemble a combination of alpha 4 and beta 2 subunits, that constitute the predominant subunits in the central nervous system. The differential inhibition and potentiation of nAChR, together with the high sensitivity, are of interest with respect to Pb2+ neurotoxicity.
authors.affiliation: Research Institute of Toxicology, Utrecht University, Netherlands. m.oortgiesen@ritox.dgk.ruu.nl
authors.forename: M
authors.initials: M
authors.lastname: Oortgiesen
authors.forename: R G
authors.initials: RG
authors.lastname: van Kleef
authors.forename: H P
authors.initials: HP
authors.lastname: Vijverberg
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D002460:Cell Line; D004558:Electric Stimulation; D004594:Electrophysiology; D007854:Lead / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D011978:Receptors, Nicotinic; D007854:Lead; D000109:Acetylcholine