INORGANIC LEAD MAY INHIBIT NEURITE DEVELOPMENT IN CULTURED RAT HIPPOCAMPAL-NEURONS THROUGH HYPERPHOSPHORYLATION
INORGANIC LEAD MAY INHIBIT NEURITE DEVELOPMENT IN CULTURED RAT HIPPOCAMPAL-NEURONS THROUGH HYPERPHOSPHORYLATION
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DOI：
10.1006/taap.1995.1174
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发表时间：
1995-09-01
影响因子：
3.8
通讯作者：
AUDESIRK, G
中科院分区：
文献类型：
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作者：
KERN, M;AUDESIRK, G
无机铅在低至100 nM的浓度下抑制培养大鼠海马神经元的神经突起始。相互矛盾的报告表明，Pb2+可能刺激或抑制蛋白激酶C、腺苷酸环化酶、磷酸二酯酶和钙调蛋白，或增加细胞内游离Ca2+浓度。因此，Pb2+可能改变Ca2+/钙调素依赖性蛋白激酶（CaM激酶）或蛋白激酶C或a的活性。我们在100 nM内单独培养大鼠海马神经元，或与激酶或钙调素抑制剂联合培养。用calphostin C抑制蛋白激酶C加重了PbCl2对神经突形成的抑制作用，而用KT5720抑制蛋白激酶A、用KN62抑制CaM激酶或用calmodulin calmidazolium抑制蛋白激酶A完全逆转了PbCl2的作用。这些结果表明，Pb2+可能通过不适当地刺激CaM激酶或环amp依赖性蛋白激酶（PKA）的蛋白磷酸化（可能是通过刺激钙调素）来抑制神经突的形成，这一假设得到了其他应该增加蛋白磷酸化的治疗（冈田酸，一种蛋白磷酸酶抑制剂，s -p- camp，一种PKA激活剂）也会减少神经突的形成的支持。在4、12、24或48小时，100 nM PbCl2对全细胞胞内游离Ca2+离子浓度没有显著改变。因此，Pb2+暴露对钙调蛋白、CaM激酶或PKA的假设刺激效应可能不是由全细胞胞内游离Ca2+的增加引起的，但可能归因于细胞内Pb2+或局部[Ca2+]的增加(i)，这在全细胞测量中没有反映出来。(C) 1995学术出版社，Inc。
Inorganic lead inhibits neurite initiation in cultured rat hippocampal neurons at concentrations as low as 100 nM. Conflicting reports suggest that Pb2+ may stimulate or inhibit protein kinase C, adenylyl cyclase, phosphodiesterase, and calmodulin, or increase intracellular free Ca2+ concentrations. Therefore, Pb2+ may alter the activities of Ca2+/calmodulin-dependent protein kinase (CaM kinase) or protein kinases C or A. We cultured rat hippocampal neurons in 100 nM PbCl2 alone or in combination with kinase or calmodulin inhibitors. Inhibiting protein kinase C with calphostin C exacerbated the inhibition of neurite initiation caused by PbCl2, but inhibiting protein kinase A with KT5720, CaM kinase with KN62, or calmodulin with calmidazolium completely reversed the effects of PbCl2. These results indicate that Pb2+ may inhibit neurite initiation by inappropriately stimulating protein phosphorylation by CaM kinase or cyclic AMP-dependent protein kinase (PKA), possibly by stimulating calmodulin, This hypothesis is supported by findings that other treatments that should increase protein phosphorylation (okadaic acid, a protein phosphatase inhibitor, and S-p-cAMPS, a PKA activator) also reduced neurite initiation. Whole-cell intracellular free Ca2+ ion concentrations were not significantly altered by 100 nM PbCl2 at 4, 12, 24, or 48 hr, Therefore, the hypothesized stimulatory effects of Pb2+ exposure on calmodulin, CaM kinase, or PKA are probably not caused by increases in whole-cell intracellular free Ca2+, but may be attributable either to intracellular Pb2+ or to localized increases in [Ca2+](i), that are not reflected in whole-cell measurements. (C) 1995 Academic Press, Inc.