Cellular aspects of persistent neurotoxicants: effects of Pb2+ on neuronal nicotinic acetylcholine receptors.
Among persistent neurotoxicants inorganic lead (Pb2+) is known to cause a variety of cellular effects associated with alterations in neuronal performance. Here we describe differential effects of Pb2+ on distinct subtypes of neuronal nicotinic acetylcholine receptors (nAChR) in Xenopus oocytes expressing various combinations of alpha and beta receptor subunits. Transient inward currents evoked by ACh in voltage clamped oocytes expressing alpha4beta2 and alpha3beta4 nAChR are inhibited by external Pb2+ at concentrations in the range of 1 nM-200 microM. The sensitivities of oocytes expressing alpha4beta2 and alpha3beta4 nAChR vary greatly. Additional experiments suggest that this variation may be due to receptor heterogeneity, which is demonstrated for alpha4beta2 nAChR in cell-attached patch clamp experiments. Conversely, the inward current evoked by ACh in oocytes expressing alpha3beta2 nAChR is potentiated by Pb2+ at concentrations in the range of 1-250 microM. The potentiating effect shows little variation between oocytes and is similar for inward currents evoked by low and high concentrations of ACh. The distinct effects on alpha3beta2 nAChR as compared to alpha4beta2 and alpha3beta4 nAChR suggest that Pb2+ interacts with both alpha and beta subunits of the neuronal nAChR. The effects of Pb2+ on defined subtypes of nAChR in oocytes are compared to those on ligand-gated ion channels in intact cells.
Zwart
R
R
Research Institute of Toxicology, Utrecht University, The Netherlands.
van Kleef
R G
RG
Van Hooft
J A
JA
Oortgiesen
M
M
Vijverberg
H P
HP
D000818:Animals; D005260:Female; D007473:Ion Channels / Q000187:drug effects; D007854:Lead / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D009865:Oocytes / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014982:Xenopus laevis
D007473:Ion Channels; D009498:Neurotoxins; D011978:Receptors, Nicotinic; D007854:Lead