针对钙病进行神经保护:关注钙通道 Cav1、Orai1 和 P2X7

IF 4.3 2区 生物学 Q2 CELL BIOLOGY
Myriam Torres-Rico , Virginia García-Calvo , Adrián Gironda-Martínez , Jorge Pascual-Guerra , Antonio G. García , Victoria Maneu
{"title":"针对钙病进行神经保护:关注钙通道 Cav1、Orai1 和 P2X7","authors":"Myriam Torres-Rico ,&nbsp;Virginia García-Calvo ,&nbsp;Adrián Gironda-Martínez ,&nbsp;Jorge Pascual-Guerra ,&nbsp;Antonio G. García ,&nbsp;Victoria Maneu","doi":"10.1016/j.ceca.2024.102928","DOIUrl":null,"url":null,"abstract":"<div><p>As the uncontrolled entry of calcium ions (Ca<sup>2+</sup>) through plasmalemmal calcium channels is a cell death trigger, the conjecture is here raised that mitigating such an excess of Ca<sup>2+</sup> entry should rescue from death the vulnerable neurons in neurodegenerative diseases (NDDs). However, this supposition has failed in some clinical trials (CTs). Thus, a recent CT tested whether isradipine, a blocker of the Cav1 subtype of voltage-operated calcium channels (VOCCs), exerted a benefit in patients with Parkinson's disease (PD); however, outcomes were negative. This is one more of the hundreds of CTs done under the principle of one-drug-one-target, that have failed in Alzheimer's disease (AD) and other NDDs during the last three decades. As there are myriad calcium channels to let Ca<sup>2+</sup> ions gain the cell cytosol, it seems reasonable to predict that blockade of Ca<sup>2+</sup> entry through a single channel may not be capable of preventing the Ca<sup>2+</sup> flood of cells by the uncontrolled Ca<sup>2+</sup> entry. Furthermore, as Ca<sup>2+</sup> signaling is involved in the regulation of myriad functions in different cell types, it seems also reasonable to guess that a therapy should be more efficient by targeting different cells with various drugs. Here, we propose to mitigate Ca<sup>2+</sup> entry by the simultaneous partial blockade of three quite different subtypes of plasmalemmal calcium channels that is, the Cav1 subtype of VOCCs, the Orai1 store-operated calcium channel (SOCC), and the purinergic P2X7 calcium channel. All three channels are expressed in both microglia and neurons. Thus, by targeting the three channels with a combination of three drug blockers we expect favorable changes in some of the pathogenic features of NDDs, namely (i) to mitigate Ca<sup>2+</sup> entry into microglia; (ii) to decrease the Ca<sup>2+</sup>-dependent microglia activation; (iii) to decrease the sustained neuroinflammation; (iv) to decrease the uncontrolled Ca<sup>2+</sup> entry into neurons; (v) to rescue vulnerable neurons from death; and (vi) to delay disease progression. In this review we discuss the arguments underlying our triad hypothesis in the sense that the combination of three repositioned medicines targeting Cav1, Orai1, and P2X7 calcium channels could boost neuroprotection and delay the progression of AD and other NDDs.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0143416024000861/pdfft?md5=11c1d21faaeacd324f82d6a1903836b4&pid=1-s2.0-S0143416024000861-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Targeting calciumopathy for neuroprotection: focus on calcium channels Cav1, Orai1 and P2X7\",\"authors\":\"Myriam Torres-Rico ,&nbsp;Virginia García-Calvo ,&nbsp;Adrián Gironda-Martínez ,&nbsp;Jorge Pascual-Guerra ,&nbsp;Antonio G. García ,&nbsp;Victoria Maneu\",\"doi\":\"10.1016/j.ceca.2024.102928\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>As the uncontrolled entry of calcium ions (Ca<sup>2+</sup>) through plasmalemmal calcium channels is a cell death trigger, the conjecture is here raised that mitigating such an excess of Ca<sup>2+</sup> entry should rescue from death the vulnerable neurons in neurodegenerative diseases (NDDs). However, this supposition has failed in some clinical trials (CTs). Thus, a recent CT tested whether isradipine, a blocker of the Cav1 subtype of voltage-operated calcium channels (VOCCs), exerted a benefit in patients with Parkinson's disease (PD); however, outcomes were negative. This is one more of the hundreds of CTs done under the principle of one-drug-one-target, that have failed in Alzheimer's disease (AD) and other NDDs during the last three decades. As there are myriad calcium channels to let Ca<sup>2+</sup> ions gain the cell cytosol, it seems reasonable to predict that blockade of Ca<sup>2+</sup> entry through a single channel may not be capable of preventing the Ca<sup>2+</sup> flood of cells by the uncontrolled Ca<sup>2+</sup> entry. Furthermore, as Ca<sup>2+</sup> signaling is involved in the regulation of myriad functions in different cell types, it seems also reasonable to guess that a therapy should be more efficient by targeting different cells with various drugs. Here, we propose to mitigate Ca<sup>2+</sup> entry by the simultaneous partial blockade of three quite different subtypes of plasmalemmal calcium channels that is, the Cav1 subtype of VOCCs, the Orai1 store-operated calcium channel (SOCC), and the purinergic P2X7 calcium channel. All three channels are expressed in both microglia and neurons. Thus, by targeting the three channels with a combination of three drug blockers we expect favorable changes in some of the pathogenic features of NDDs, namely (i) to mitigate Ca<sup>2+</sup> entry into microglia; (ii) to decrease the Ca<sup>2+</sup>-dependent microglia activation; (iii) to decrease the sustained neuroinflammation; (iv) to decrease the uncontrolled Ca<sup>2+</sup> entry into neurons; (v) to rescue vulnerable neurons from death; and (vi) to delay disease progression. In this review we discuss the arguments underlying our triad hypothesis in the sense that the combination of three repositioned medicines targeting Cav1, Orai1, and P2X7 calcium channels could boost neuroprotection and delay the progression of AD and other NDDs.</p></div>\",\"PeriodicalId\":9678,\"journal\":{\"name\":\"Cell calcium\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.3000,\"publicationDate\":\"2024-07-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0143416024000861/pdfft?md5=11c1d21faaeacd324f82d6a1903836b4&pid=1-s2.0-S0143416024000861-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell calcium\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0143416024000861\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell calcium","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0143416024000861","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

由于钙离子(Ca2+)通过质膜钙通道不受控制地进入细胞是导致细胞死亡的诱因,因此有人提出这样的猜想,即缓解 Ca2+ 的过量进入应能挽救神经退行性疾病(NDDs)中脆弱的神经元免于死亡。然而,这一推测在一些临床试验(CT)中失败了。因此,最近的一项临床试验测试了电压操作钙通道(VOCCs)Cav1 亚型的阻断剂异拉地平是否对帕金森病(PD)患者有益,但结果是否定的。在过去三十年中,按照一药一靶点的原则进行了数百例 CT,但在阿尔茨海默病(AD)和其他 NDDs 中均告失败。由于有无数的钙通道让 Ca2+ 离子进入细胞胞浆,因此似乎可以合理地预测,通过单一通道阻断 Ca2+ 进入细胞可能无法防止 Ca2+ 不受控制地进入细胞而导致 Ca2+ 泛滥。此外,由于 Ca2+ 信号传导参与了不同类型细胞中无数功能的调控,我们似乎也有理由推测,针对不同细胞使用不同药物的疗法应该更有效。在这里,我们建议通过同时部分阻断三种截然不同亚型的浆膜钙通道(即 VOCCs 的 Cav1 亚型、Orai1 储存操作钙通道(SOCC)和嘌呤能 P2X7 钙通道)来缓解 Ca2+ 的进入。这三种通道在小胶质细胞和神经元中均有表达。因此,通过使用三种药物阻断剂联合靶向这三种通道,我们预计 NDDs 的一些致病特征会发生有利的变化,即:(i) 减轻 Ca2+ 进入小胶质细胞;(ii) 减少 Ca2+ 依赖性小胶质细胞激活;(iii) 减少持续的神经炎症;(iv) 减少不受控制的 Ca2+ 进入神经元;(v) 挽救脆弱的神经元免于死亡;(vi) 延缓疾病进展。在这篇综述中,我们讨论了我们的三联假说的基本论点,即针对 Cav1、Orai1 和 P2X7 钙通道的三种重新定位药物的组合可以增强神经保护作用并延缓 AD 和其他 NDD 的进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting calciumopathy for neuroprotection: focus on calcium channels Cav1, Orai1 and P2X7

Targeting calciumopathy for neuroprotection: focus on calcium channels Cav1, Orai1 and P2X7

As the uncontrolled entry of calcium ions (Ca2+) through plasmalemmal calcium channels is a cell death trigger, the conjecture is here raised that mitigating such an excess of Ca2+ entry should rescue from death the vulnerable neurons in neurodegenerative diseases (NDDs). However, this supposition has failed in some clinical trials (CTs). Thus, a recent CT tested whether isradipine, a blocker of the Cav1 subtype of voltage-operated calcium channels (VOCCs), exerted a benefit in patients with Parkinson's disease (PD); however, outcomes were negative. This is one more of the hundreds of CTs done under the principle of one-drug-one-target, that have failed in Alzheimer's disease (AD) and other NDDs during the last three decades. As there are myriad calcium channels to let Ca2+ ions gain the cell cytosol, it seems reasonable to predict that blockade of Ca2+ entry through a single channel may not be capable of preventing the Ca2+ flood of cells by the uncontrolled Ca2+ entry. Furthermore, as Ca2+ signaling is involved in the regulation of myriad functions in different cell types, it seems also reasonable to guess that a therapy should be more efficient by targeting different cells with various drugs. Here, we propose to mitigate Ca2+ entry by the simultaneous partial blockade of three quite different subtypes of plasmalemmal calcium channels that is, the Cav1 subtype of VOCCs, the Orai1 store-operated calcium channel (SOCC), and the purinergic P2X7 calcium channel. All three channels are expressed in both microglia and neurons. Thus, by targeting the three channels with a combination of three drug blockers we expect favorable changes in some of the pathogenic features of NDDs, namely (i) to mitigate Ca2+ entry into microglia; (ii) to decrease the Ca2+-dependent microglia activation; (iii) to decrease the sustained neuroinflammation; (iv) to decrease the uncontrolled Ca2+ entry into neurons; (v) to rescue vulnerable neurons from death; and (vi) to delay disease progression. In this review we discuss the arguments underlying our triad hypothesis in the sense that the combination of three repositioned medicines targeting Cav1, Orai1, and P2X7 calcium channels could boost neuroprotection and delay the progression of AD and other NDDs.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Cell calcium
Cell calcium 生物-细胞生物学
CiteScore
8.70
自引率
5.00%
发文量
115
审稿时长
35 days
期刊介绍: Cell Calcium covers the field of calcium metabolism and signalling in living systems, from aspects including inorganic chemistry, physiology, molecular biology and pathology. Topic themes include: Roles of calcium in regulating cellular events such as apoptosis, necrosis and organelle remodelling Influence of calcium regulation in affecting health and disease outcomes
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信