Nanomolar concentrations of lead selectively block neuronal nicotinic acetylcholine responses in mouse neuroblastoma cells.
The effects of inorganic lead (Pb2+) on the ion currents mediated by (1) neuronal nicotinic acetylcholine (ACh) receptors, (2) serotonin 5-HT3 receptors, as well as (3) voltage-dependent Ca2+ and Na+ channels have been investigated in voltage clamped mouse neuroblastoma cells. The nicotinic ACh receptor-ion channel complex appeared more sensitive to Pb2+ than the other ion channels investigated. Low concentrations of Pb2+ (1 nM - 3 microM) reduced the peak amplitude of the ACh-induced inward current to 74%-10% of the control value in a concentration-dependent manner. However, between 10 microM and 100 microM Pb2+ the blocking effect was reversed, while the decay of the ACh-induced inward current was delayed. These effects of Pb2+ on the nicotinic receptor-mediated inward current can be described by the sum of two sigmoidal concentration-effect curves with an IC50 value of 19 nM and an EC50 of 21 microM and with slope factors of -0.5 and 0.8, respectively. The current mediated by 5-HT3 receptors was less potently blocked by Pb2+ (IC50 = 49 microM; slope factor = -0.3). In addition, Pb2+ blocked the ion current through voltage-dependent Ca2+ channels. The IC50 value of the concentration-effect curve of block of transient type Ca2+ channels by Pb2+ is 4.8 microM and the slope factor is -0.9. Voltage-dependent Na+ channels were not affected by Pb2+ up to 100 microM. At concentrations greater than 1 microM, Pb2+ also induced a noninactivating inward current. The present results show that modification of neuronal nicotinic receptor function may contribute to neurotoxic effects of Pb2+ poisoning.
Oortgiesen
M
M
Research Institute of Toxicology, University of Utrecht, The Netherlands.
van Kleef
R G
RG
Bajnath
R B
RB
Vijverberg
H P
HP
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007473:Ion Channels / Q000187:drug effects*; D007854:Lead / Q000633:toxicity*; D051379:Mice; D009447:Neuroblastoma; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D014407:Tumor Cells, Cultured
D015220:Calcium Channels; D007473:Ion Channels; D011978:Receptors, Nicotinic; D015222:Sodium Channels; D007854:Lead; D012701:Serotonin; D000109:Acetylcholine