The C-terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death:: involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways
The C-terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death:: involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways
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DOI：
10.1111/j.1471-4159.2004.02586.x
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发表时间：
2004-09-01
影响因子：
4.7
通讯作者：
Aguilera, J
中科院分区：
文献类型：
--
作者：
Chaïb-Oukadour, I;Gil, C;Aguilera, J
当培养的小脑颗粒神经元从含有高细胞外钾浓度（[K+]（e））（25 mM）的培养基转移到具有较低[K+]（e）（5 mM）的培养基时，半胱天冬酶-3活性被诱导并且细胞自发死亡。相反，如果在非去极化条件下的细胞用脑源性神经营养因子（BDNF）处理，则半胱天冬酶-3活性、染色质凝聚和细胞死亡显著减少。在这项研究中，我们表明，C-末端结构域的破伤风毒素重链（HC-TeTx）是能够产生相同的神经保护作用，评估减少四唑盐和染色质凝聚。Hc-TeTx赋予的神经保护作用似乎依赖于磷脂酰肌醇3-激酶（PI 3 K）和促分裂原活化蛋白激酶，这分别由选择性抑制剂Wortmannin和PD 98059证明。Hc-TeTx还诱导酪氨酸激酶BDNF受体的磷酸化，以其GTP结合形式激活p21 Ras，以及包括细胞外信号调节激酶-1/2（ERK-1/2）、p90核糖体S6激酶（p90 rsk）和CREB（cAMP反应元件结合蛋白）的级联的磷酸化。另一方面，还检测到Akt途径的激活以及半胱天冬酶-3的活性形式的抑制。这些结果表明，Hc-TeTx促进小脑颗粒细胞存活的PI 3 K和ERK依赖性途径都有意义。
When cultured cerebellar granule neurones are transferred from a medium containing high extracellular potassium concentration ([K+](e)) (25 mM) to one with lower [K+](e) (5 mM), caspase-3 activity is induced and cells die apoptotically. In contrast, if cells in non-depolarizing conditions are treated with brain-derived neurotrophic factor (BDNF), caspase-3 activity, chromatin condensation and cell death are markedly diminished. In this study, we show that the C-terminal domain of the tetanus toxin heavy-chain (Hc-TeTx) is able to produce the same neuroprotective effect, as assessed by reduction of tetrazolium salts and by chromatin condensation. Hc-TeTx-conferred neuroprotection appears to depend on phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase, as is demonstrated by the selective inhibitors Wortmannin and PD98059, respectively. Hc-TeTx also induces phosphorylation of the tyrosine kinase BDNF receptor, activation of p21Ras in its GTP-bound form, and phosphorylation of the cascade including extracellular-signal-regulated kinases-1/2 (ERK-1/2), p90 ribosomal S6 kinase (p90rsk) and CREB (cAMP-response-element-binding protein). On the other hand, activation of the Akt pathway is also detected, as well as inhibition of the active form of caspase-3. These results point to an implication of both PI3K- and ERK-dependent pathways in the promotion of cerebellar granule cell survival by Hc-TeTx.