Zwart R, van Kleef R G, Van Hooft J A, Oortgiesen M, Vijverberg H P
Research Institute of Toxicology, Utrecht University, The Netherlands.
Neurotoxicology. 1997;18(3):709-17.
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.
在持久性神经毒物中，无机铅（Pb2+）已知会引起多种与神经元功能改变相关的细胞效应。在此，我们描述了Pb2+对非洲爪蟾卵母细胞中不同亚型神经元烟碱型乙酰胆碱受体（nAChR）的差异效应，这些卵母细胞表达了α和β受体亚基的各种组合。在表达α4β2和α3β4 nAChR的电压钳制卵母细胞中，乙酰胆碱（ACh）诱发的瞬时内向电流在1 nM - 200 μM浓度范围内受到外部Pb2+的抑制。表达α4β2和α3β4 nAChR的卵母细胞的敏感性差异很大。进一步的实验表明，这种差异可能是由于受体的异质性，这在细胞贴附式膜片钳实验中已针对α4β2 nAChR得到证实。相反，在表达α3β2 nAChR的卵母细胞中，ACh诱发的内向电流在1 - 250 μM浓度范围内受到Pb2+的增强。这种增强效应在卵母细胞之间变化很小，并且对于低浓度和高浓度ACh诱发的内向电流相似。与α4β2和α3β4 nAChR相比，Pb2+对α3β2 nAChR的独特效应表明，Pb2+与神经元nAChR的α和β亚基均相互作用。将Pb2+对卵母细胞中特定nAChR亚型的效应与对完整细胞中配体门控离子通道 的效应进行了比较。
