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 , Virginia García-Calvo , Adrián Gironda-Martínez , Jorge Pascual-Guerra , Antonio G. García , 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 , Virginia García-Calvo , Adrián Gironda-Martínez , Jorge Pascual-Guerra , Antonio G. García , 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}
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.
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