Targeting individual calpain isoforms for neuroprotection.
Targeting individual calpain isoforms for neuroprotection.
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DOI：
10.1016/j.expneurol.2010.07.025
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发表时间：
2010-11
影响因子：
5.3
通讯作者：
Saatman, Kathryn E.
中科院分区：
文献类型：
--
作者：
Geddes, James W.;Saatman, Kathryn E.
钙蛋白酶过度激活与多种神经系统疾病和神经退行性疾病引起的神经退行性病变有关，包括中风、创伤性脑和脊髓损伤以及阿尔茨海默氏病（Bevers 和 Neumar，2008；Saatman 等，2010；Vosler 等，2008）。最具特征的钙蛋白酶，以及在中枢神经系统中占主导地位的钙蛋白酶，是普遍存在的 m-和 μ-钙蛋白酶。这两种异构体之间的主要区别是纯化酶对 Ca2+ 的需求，m-钙蛋白酶需要毫摩尔 Ca2+ 才能激活，而 μ-钙蛋白酶则需要微摩尔 Ca2+ (Dayton, 1982)。 CNS 中存在的其他钙蛋白酶包括 3、5、10 和 12（Konig 等，2003；Ma 等，2001；Shin 等，2004；Waghray 等，2004），尽管它们的作用和相对活性很大程度上未知。虽然钙蛋白酶过度激活导致神经退行性变，但钙蛋白酶也发挥重要的生理作用，包括信号转导、细胞迁移、膜融合、细胞分化。因此，挑战是抑制钙蛋白酶过度激活的病理后果，但保留钙蛋白酶功能的生理方面。一种方法是识别具有显着病理作用的钙蛋白酶亚型，而不是那些对生理钙蛋白酶功能至关重要的亚型。激活麦钙蛋白酶所需的高 Ca2+ 水平可能仅在病理条件下才会遇到；因此，mcalpain 被假设为代表一种病理亚型。然而，m-钙蛋白酶可能被体内低得多的 Ca2+ 水平或包括营养因子在内的非 Ca2+ 机制激活（Goll 等，2003；Zadran 等，2010）。另外，μ-钙蛋白酶作为病理亚型的支持是基于其分布及其裂解底物αII-血影蛋白在中枢神经系统损伤后的分布（Grynspan 等，1997；Hamakubo 等，1986；Roberts-Lewis 等，1994；Siman 等，1985）。然而，两种钙蛋白酶同工型的底物高度相似，至少在体外是如此，并且小分子钙蛋白酶抑制剂以相似的效力抑制两种同工型（Goll 等，2003；Wang 和 Yuen，1999）。因此，很难确定这两种普遍存在的钙蛋白酶亚型的不同作用。
Calpain overactivation is implicated in the neurodegeneration resulting from a wide range of neurologic disorders and neurodegen-erative conditions including stroke, traumatic brain and spinal cord injury, and Alzheimer’s disease (Bevers and Neumar, 2008; Saatman et al., 2010; Vosler et al., 2008). The best-characterized calpains, and those predominant in the CNS, are the ubiquitous m-and μ-calpains. A major difference between these two isoforms is the Ca2+ requirement of the purified enzymes, with m-calpain requiring millimolar Ca2+ for activation as compared to micromolar Ca2+ for μ-calpain (Dayton, 1982). Other calpains present in the CNS include 3, 5, 10, and 12 (Konig et al., 2003; Ma et al., 2001; Shin et al., 2004; Waghray et al., 2004), although their roles and relative activities are largely unknown.While calpain overactivation contributes to neurodegeneration, calpains also serve essential physiological roles including signal transduction, cell migration, membrane fusion, and cell differentiation. Thus, the challenge is to inhibit the pathological consequences of calpain overactivation but preserve physiologic aspects of calpain function. One approach is to identify calpain isoforms with a prominent pathological role, as opposed to those which are essential for physiological calpain functions. The high Ca2+ levels required to activate mcalpain would presumably only be encountered under pathologic conditions; therefore mcalpain has been hypothesized to represent a pathologic isoform. However, m-calpain may be activated by much lower Ca2+ levels in vivo or by non-Ca2+ mechanisms including trophic factors (Goll et al., 2003; Zadran et al., 2010). Alternatively, support for μ-calpain as a pathologic isoform was based on its distribution and that of its cleaved substrate, αII-spectrin, following CNS insults (Grynspan et al., 1997; Hamakubo et al., 1986; Roberts-Lewis et al., 1994; Siman et al., 1985). However, the substrates of the two calpain isoforms are highly similar, at least in vitro, and small molecule calpain inhibitors inhibit both isoforms with similar potency (Goll et al., 2003; Wang and Yuen, 1999). As a result, it has been difficult to identify distinct roles for these two ubiquitous calpain isoforms.
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影响因子：
4.7
作者：
Bevers, Matthew B.;Lawrence, Eric;Neumar, Robert W.
通讯作者：
Neumar, Robert W.
影响因子：
2.8
作者：
König, N;Raynaud, F;Benyamin, Y
通讯作者：
Benyamin, Y
影响因子：
4.8
作者：
Zhang, WL;Lane, RD;Mellgren, RL
通讯作者：
Mellgren, RL
DOI：
10.1016/j.nurt.2009.11.002
发表时间：
2010-01
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Saatman KE;Creed J;Raghupathi R
通讯作者：
Raghupathi R
DOI：
10.1523/jneurosci.5120-09.2010
发表时间：
2010-01-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Zadran S;Jourdi H;Rostamiani K;Qin Q;Bi X;Baudry M
通讯作者：
Baudry M