Substance P provides neuroprotection in cerebellar granule cells through Akt and MAPK/Erk activation: Evidence for the involvement of the delayed rectifier potassium current
Substance P provides neuroprotection in cerebellar granule cells through Akt and MAPK/Erk activation: Evidence for the involvement of the delayed rectifier potassium current
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DOI：
10.1016/j.neuropharm.2007.01.020
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发表时间：
2007-05-01
影响因子：
4.7
通讯作者：
Severini, C.
中科院分区：
文献类型：
--
作者：
Amadoro, G.;Pieri, M.;Severini, C.
在本研究中，我们评价了P物质(SP)和其他神经激肽I受体(NK1)激动剂以剂量和时间依赖的方式保护原代培养的大鼠小脑颗粒细胞(CGCs)免受血清和钾剥夺诱导的细胞死亡(S-K5)的能力。我们还证实了SP高亲和力NK1转录本的存在以及NK1蛋白在CGCs亚群的膜上的定位。此外，Western印迹分析表明，SP可显著抑制S-K5诱导的Akt1/2和ERK1/2去磷酸化，且呈剂量依赖性。令人惊讶的是，在SP处理的CGCs中，caspase-3的活性没有受到抑制，而calain-1的活性却适度降低。证实这一结果的是，SP阻断了Calain介导的tau蛋白的切割，Western印迹分析表明，17 kDa的诊断片段出现的减少。此外，在用去极化电位阶跃诱发的神经元中，约42%的神经元上的延迟整流钾电流(I-k)被SP引起显著降低。综上所述，本研究结果表明，在CGCs中表达的NK1受体的激活可能通过Akt和Erk激活途径以及通过抑制Ik而促进神经元存活，从而发挥其神经保护作用。(C)2007年由爱思唯尔有限公司出版。
In the current study, we have evaluated the ability of substance P (SP) and other neurokinin I receptor (NK1) agonists to protect, in a dose-and time-dependent manner, primary cultures of rat cerebellar granule cells (CGCs) from serum and potassium deprivation-induced cell death (S-K5). We also established the presence of SP high affinity NK1 transcripts and the NK1 protein localization in the membrane of a sub-population of CGCs. Moreover, SP significantly and dose-dependently reduced the Akt 1/2 and Erk1/2 dephosphorylation induced by S-K5 conditions, as demonstrated by Western blot analysis. Surprisingly, in SP-treated CGCs caspase-3 activity was not inhibited, while the calpain-1 activity was moderately reduced. Corroborating this result, SP blocked calpain-mediated cleavage of tau protein, as demonstrated by the reduced appearance of a diagnostic fragment of 17 kDa by Western blot analysis. In addition, SP induced a significant reduction of the delayed rectifier K+ currents (I-k) in about 42% of the patched neurons, when these were evoked with depolarizing potential steps. Taken together, the present results demonstrate that the activation of NK1 receptors expressed in CGCs promote the neuronal survival via pathways involving Akt and Erk activation and by inhibition Of Ik which can contribute to the neuroprotective effect of the peptide. (C) 2007 Published by Elsevier Ltd.