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冈田酸(一种蛋白磷酸酶抑制剂)的神经毒性和突触效应

Neurotoxic and synaptic effects of okadaic acid, an inhibitor of protein phosphatases.

作者信息

Tapia R, Peña F, Arias C

机构信息

Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, DF, México.

出版信息

Neurochem Res. 1999 Nov;24(11):1423-30. doi: 10.1023/a:1022588808260.

Abstract

Protein phosphorylation and dephosphorylation reactions, catalyzed by kinases and phosphatases, are involved in the regulation of a wide variety of physiological processes. In the nervous system, such reactions seem to modulate the function of several proteins crucial in synaptic transmission, including voltage-gated and ligand-gated channels, neurotransmitter release, and neurotransmitter transporters. On the other hand, hyperphosphorylation of certain cytoskeletal proteins or receptors may lead to neuronal death. In the present work we review the neurotoxic effect of okadaic acid (OKA), a potent and specific inhibitor of the serine/threonine protein phosphatases 1 and 2A, as well as its action on synaptic function. We analyze recent findings demonstrating that the microinjection of OKA in rat hippocampus induces neuronal stress, hyperexcitation and neurodegeneration, and discuss their possible relationships to alterations of protein phosphorylation-dephosphorylation observed in Alzheimer's disease brain. These results suggest that protein hyperphosphorylation due to inhibition of phosphatases in vivo induces neuronal stress and subsequent neurodegeneration.

摘要

由激酶和磷酸酶催化的蛋白质磷酸化和去磷酸化反应参与多种生理过程的调节。在神经系统中,此类反应似乎可调节突触传递中几种关键蛋白质的功能,包括电压门控通道和配体门控通道、神经递质释放以及神经递质转运体。另一方面,某些细胞骨架蛋白或受体的过度磷酸化可能导致神经元死亡。在本研究中,我们综述了冈田酸(OKA)的神经毒性作用,它是丝氨酸/苏氨酸蛋白磷酸酶1和2A的强效特异性抑制剂,以及其对突触功能的作用。我们分析了最近的研究结果,这些结果表明向大鼠海马体微量注射OKA会诱导神经元应激、过度兴奋和神经退行性变,并讨论了它们与阿尔茨海默病大脑中观察到的蛋白质磷酸化-去磷酸化改变的可能关系。这些结果表明,体内磷酸酶抑制导致的蛋白质过度磷酸化会诱导神经元应激及随后的神经退行性变。

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