In vitro approaches to species and receptor diversity in cellular neurotoxicology

Effects of selective and non-selective neurotoxic compounds on membrane currents mediated by nicotinic acetylcholine receptors (nAChR), natively expressed in cultured cells and artificially expressed in Xenopus oocytes, have been investigated in vitro using voltage clamp techniques. Mammalian neuronal nAChR in cultured mouse N1E-115 cells, muscle type nAChR in cultured mouse BC3H1 cells and insect neuronal nAChR in dissociated locust thoracic ganglion neurons show interspecies differences in sensitivity to neurotoxic compounds. The nitromethylene heterocyclic insecticide WL145004 and physostigmine selectively agonize the insect type nAChR. The mouse neuronal and muscle types of nAChR are much less sensitive to and are partially inhibited by WL 145004. Intraspecies differences have been investigated for the effects of Pb(2+) on subtypes of nAChR expressed in Xenopus oocytes. The nature of the effect of the heavy metal Pb(2+) depends on the combination of mammalian neuronal a and beta nAChR subunits. Ion currents mediated by alpha4beta2 and alpha3beta4 nAChR are inhibited and those mediated by alpha3beta2 nAChR are potentiated by Pb(2+). Distinct sensitivities of subtypes of mammalian neuronal nAChR to agonists and antagonists are employed to characterize native nAChR in N 1E-115 cells. Implications of receptor diversity for neurotoxicology are discussed.