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“Gatekeepers of heaven” breaking bad "天国守门人 "坏了
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-21 DOI: 10.1016/j.ceca.2023.102842
Hwei Ling Ong, Indu S. Ambudkar
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引用次数: 0
Two-pore channels (TPCs) acts as a hub for excitation-contraction coupling, metabolism and cardiac hypertrophy signalling 双孔通道(TPC)是兴奋-收缩耦合、新陈代谢和心脏肥大信号的枢纽
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-16 DOI: 10.1016/j.ceca.2023.102839
Antoine de Zélicourt , Abdallah Fayssoil , Arnaud Mansart , Faouzi Zarrouki , Ahmed Karoui , Jérome Piquereau , Florence Lefebvre , Pascale Gerbaud , Delphine Mika , Mbarka Dakouane-Giudicelli , Erwan Lanchec , Miao Feng , Véronique Leblais , Régis Bobe , Jean-Marie Launay , Antony Galione , Ana Maria Gomez , Sabine de la Porte , José-Manuel Cancela

Ca2+ signaling is essential for cardiac contractility and excitability in heart function and remodeling. Intriguingly, little is known about the role of a new family of ion channels, the endo-lysosomal non-selective cation “two-pore channel” (TPCs) in heart function. Here we have used double TPC knock-out mice for the 1 and 2 isoforms of TPCs (Tpcn1/2−/−) and evaluated their cardiac function. Doppler-echocardiography unveils altered left ventricular (LV) systolic function associated with a LV relaxation impairment. In cardiomyocytes isolated from Tpcn1/2−/- mice, we observed a reduction in the contractile function with a decrease in the sarcoplasmic reticulum Ca2+ content and a reduced expression of various key proteins regulating Ca2+ stores, such as calsequestrin. We also found that two main regulators of the energy metabolism, AMP-activated protein kinase and mTOR, were down regulated. We found an increase in the expression of TPC1 and TPC2 in a model of transverse aortic constriction (TAC) mice and in chronically isoproterenol infused WT mice. In this last model, adaptive cardiac hypertrophy was reduced by Tpcn1/2 deletion. Here, we propose a central role for TPCs and lysosomes that could act as a hub integrating information from the excitation-contraction coupling mechanisms, cellular energy metabolism and hypertrophy signaling.

在心脏功能和重塑过程中,Ca2+ 信号对心脏收缩力和兴奋性至关重要。耐人寻味的是,人们对一个新的离子通道家族--内溶酶体非选择性阳离子 "双孔通道"(TPCs)--在心脏功能中的作用知之甚少。在这里,我们使用了双TPC基因敲除小鼠(Tpcn1/2-/-),并对其心脏功能进行了评估。多普勒超声心动图显示,左心室收缩功能的改变与左心室松弛功能受损有关。在分离自 Tpcn1/2-/- 小鼠的心肌细胞中,我们观察到收缩功能下降,肌质网 Ca2+ 含量减少,各种调节 Ca2+ 储存的关键蛋白(如钙sequestrin)表达减少。我们还发现,能量代谢的两个主要调节因子--AMP 激活的蛋白激酶和 mTOR--也受到了下调。我们发现,在横纹主动脉缩窄(TAC)小鼠模型和长期注射异丙肾上腺素的 WT 小鼠中,TPC1 和 TPC2 的表达均有所增加。在最后一个模型中,Tpcn1/2 基因缺失会导致适应性心肌肥大减轻。在此,我们提出了 TPCs 和溶酶体的核心作用,它们可以作为一个枢纽,整合来自兴奋-收缩耦合机制、细胞能量代谢和肥大信号的信息。
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引用次数: 0
Calcium influx into astrocytes plays a pivotal role in inflammation-driven behaviors 钙流入星形胶质细胞在炎症驱动行为中起着关键作用
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-05 DOI: 10.1016/j.ceca.2023.102838
Alfonso Martín-Peña, Malú Gámez Tansey
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引用次数: 0
TRPV2 inhibitor tranilast prevents atrial fibrillation in rat models of pulmonary hypertension TRPV2 抑制剂氨曲司特能预防肺动脉高压大鼠模型中的心房颤动
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-01 DOI: 10.1016/j.ceca.2023.102840
Tianxin Ye, Zhuonan Song, Yunping Zhou, Zhangchi Liu, Yi Yu, Fangcong Yu, Yanan Chu, Jiaran Shi, Longbo Wang, Cui Zhang, Xin Liu, Bo Yang, Jinxiu Yang, Xingxiang Wang
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引用次数: 0
Aromatically stacking the odds in favour of increased ORAI1 activation. 从芳香学角度看,增加 ORAI1 激活的可能性更大。
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-01 DOI: 10.1016/j.ceca.2023.102841
P. Stathopulos, M. Ikura
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引用次数: 0
The role of Ca2+-signaling in the regulation of epigenetic mechanisms Ca2+信号在表观遗传机制调控中的作用。
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-21 DOI: 10.1016/j.ceca.2023.102836
Andrés Hernández-Oliveras, Angel Zarain-Herzberg

Epigenetic mechanisms regulate multiple cell functions like gene expression and chromatin conformation and stability, and its misregulation could lead to several diseases including cancer. Epigenetic drugs are currently under investigation in a broad range of diseases, but the cellular processes involved in regulating epigenetic mechanisms are not fully understood. Calcium (Ca2+) signaling regulates several cellular mechanisms such as proliferation, gene expression, and metabolism, among others. Moreover, Ca2+ signaling is also involved in diseases such as neurological disorders, cardiac, and cancer. Evidence indicates that Ca2+ signaling and epigenetics are involved in the same cellular functions, which suggests a possible interplay between both mechanisms. Ca2+-activated transcription factors regulate the recruitment of chromatin remodeling complexes into their target genes, and Ca2+-sensing proteins modulate their activity and intracellular localization. Thus, Ca2+ signaling is an important regulator of epigenetic mechanisms. Moreover, Ca2+ signaling activates epigenetic mechanisms that in turn regulate genes involved in Ca2+ signaling, suggesting possible feedback between both mechanisms. The understanding of how epigenetics are regulated could lead to developing better therapeutical approaches.

表观遗传机制调节多种细胞功能,如基因表达、染色质构象和稳定性,其失调可能导致包括癌症在内的多种疾病。表观遗传药物目前正在广泛的疾病研究中,但参与调节表观遗传机制的细胞过程尚未完全了解。钙(Ca2+)信号调节多种细胞机制,如增殖、基因表达和代谢等。此外,Ca2+信号还与神经系统疾病、心脏病和癌症等疾病有关。有证据表明,Ca2+信号和表观遗传学参与相同的细胞功能,这表明两种机制之间可能存在相互作用。Ca2+激活的转录因子调节染色质重塑复合物进入靶基因的募集,Ca2+感应蛋白调节其活性和细胞内定位。因此,Ca2+信号是表观遗传机制的重要调节因子。此外,Ca2+信号激活表观遗传机制,而表观遗传机制反过来调节参与Ca2+信号传导的基因,这表明两种机制之间可能存在反馈。理解表观遗传学是如何被调控的可能会导致开发更好的治疗方法。
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引用次数: 0
Nanojunctions: Specificity of Ca2+ signaling requires nano-scale architecture of intracellular membrane contact sites 纳米连接:Ca2+信号的特异性需要细胞膜内接触位点的纳米级结构
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-19 DOI: 10.1016/j.ceca.2023.102837
Nicola Fameli , Cornelis van Breemen , Klaus Groschner

Spatio-temporal definition of Ca2+ signals involves the assembly of signaling complexes within the nano-architecture of contact sites between the sarco/endoplasmic reticulum (SR/ER) and the plasma membrane (PM). While the requirement of precise spatial assembly and positioning of the junctional signaling elements is well documented, the role of the nano-scale membrane architecture itself, as an ion-reflecting confinement of the signalling unit, remains as yet elusive. Utilizing the Na+/Ca2+ Exchanger-1 / SR/ER Ca2+ ATPase-2-mediated ER Ca2+ refilling process as a junctional signalling paradigm, we provide here the first evidence for an indispensable cellular function of the junctional membrane architecture. Our stochastic modeling approach demonstrates that junctional ER Ca2+ refilling operates exclusively at nano-scale membrane spacing, with a strong inverse relationship between junctional width and signaling efficiency. Our model predicts a breakdown of junctional Ca2+ signaling with loss of reflecting membrane confinement. In addition we consider interactions between Ca2+ and the phospholipid membrane surface, which may support interfacial Ca2+ transport and promote receptor targeting. Alterations in the molecular and nano-scale membrane organization at organelle-PM contacts are suggested as a new concept in pathophysiology.

Ca2+信号的时空定义涉及信号复合物在sarco/endoplasmic网(SR/ER)和质膜(PM)之间接触位点的纳米结构内的组装。虽然对连接信号元件的精确空间组装和定位的要求已经得到了充分的证明,但纳米级膜结构本身作为信号单元的离子反射限制的作用仍然难以捉摸。利用Na+/Ca2+ exchange -1 / SR/ER Ca2+ atpase -2介导的ER Ca2+再填充过程作为连接信号范式,我们在这里提供了连接膜结构不可或缺的细胞功能的第一个证据。我们的随机建模方法表明,结ER Ca2+再填充仅在纳米级膜间距下进行,结宽度和信号传导效率之间存在很强的反比关系。我们的模型预测了连接Ca2+信号的分解与反射膜约束的损失。此外,我们考虑Ca2+和磷脂膜表面之间的相互作用,这可能支持界面Ca2+运输和促进受体靶向。细胞器- pm接触时分子和纳米尺度膜组织的改变是病理生理学中的一个新概念。
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引用次数: 0
Development of chemical tools based on GSK-7975A to study store-operated calcium entry in cells 基于GSK-7975A的化学工具的开发,用于研究储存操作的钙进入细胞
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-15 DOI: 10.1016/j.ceca.2023.102834
Dominic Tscherrig , Rajesh Bhardwaj , Daniel Biner , Jan Dernič , Daniela Ross-Kaschitza , Christine Peinelt , Matthias A. Hediger , Martin Lochner

Many physiological functions, such as cell differentiation, proliferation, muscle contraction, neurotransmission and fertilisation, are regulated by changes of Ca2+ levels. The major Ca2+ store in cells is the endoplasmic reticulum (ER). Certain cellular processes induce ER store depletion, e.g. by activating IP3 receptors, that in turn induces a store refilling process known as store-operated calcium entry (SOCE). This refilling process entails protein-protein interactions between Ca2+ sensing stromal interaction molecules (STIM) in the ER membrane and Orai proteins in the plasma membrane. Fully assembled STIM/Orai complexes then form highly selective Ca2+ channels called Ca2+ release-activated Ca2+ Channels (CRAC) through which Ca2+ ions flow into the cytosol and subsequently are pumped into the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Abnormal SOCE has been associated with numerous human diseases and cancers, and therefore key players STIM and Orai have attracted significant therapeutic interest. Several potent experimental and clinical candidate compounds have been developed and have helped to study SOCE in various cell types. We have synthesized multiple novel small-molecule probes based on the known SOCE inhibitor GSK-7975A. Here we present GSK-7975A derivatives, which feature photo-caging, photo-crosslinking, biotin and clickable moieties, and also contain deuterium labels. Evaluation of these GSK-7975A probes using a fluorometric imaging plate reader (FLIPR)-Tetra-based Ca2+ imaging assay showed that most synthetic modifications did not have a detrimental impact on the SOCE inhibitory activity. The photo-caged GSK-7975A was also used in patch-clamp electrophysiology experiments. In summary, we have developed a number of active, GSK-7975A-based molecular probes that have interesting properties and therefore are useful experimental tools to study SOCE in various cells and settings.

许多生理功能,如细胞分化、增殖、肌肉收缩、神经传递和受精,都受Ca2+水平变化的调节。细胞内主要的Ca2+储存是内质网(ER)。某些细胞过程诱导内质网储存耗尽,例如通过激活IP3受体,进而诱导储存再填充过程,称为储存操作钙进入(SOCE)。这种再填充过程涉及内质膜中Ca2+感应基质相互作用分子(STIM)和质膜中的Orai蛋白之间的蛋白-蛋白相互作用。完全组装的STIM/Orai复合物然后形成高度选择性的Ca2+通道,称为Ca2+释放激活的Ca2+通道(CRAC), Ca2+离子通过该通道流入细胞质,随后被肌浆/内质网钙atp酶(SERCA)泵入内质网。异常的SOCE与许多人类疾病和癌症有关,因此主要参与者STIM和Orai引起了重大的治疗兴趣。已经开发了几种有效的实验和临床候选化合物,并有助于研究各种细胞类型中的SOCE。我们基于已知的SOCE抑制剂GSK-7975A合成了多种新型小分子探针。在这里,我们提出GSK-7975A衍生物,具有光笼化,光交联,生物素和可点击的部分,也含有氘标签。对这些GSK-7975A探针使用荧光成像板读取器(FLIPR)-基于四氢钙离子成像分析的评估显示,大多数合成修饰对SOCE抑制活性没有有害影响。光笼式GSK-7975A也用于膜片钳电生理实验。总之,我们已经开发了许多活性的、基于gsk -7975的分子探针,这些探针具有有趣的特性,因此是在各种细胞和环境中研究SOCE的有用实验工具。
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引用次数: 0
CRACing the role of calcium signaling in ILC2s 钙信号在ILC2s中的作用
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-15 DOI: 10.1016/j.ceca.2023.102835
Guido H. Falduto, Daniella M. Schwartz
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引用次数: 0
Allosteric changes in protein stability and dynamics as pathogenic mechanism for calmodulin variants not affecting Ca2+ coordinating residues 不影响Ca2+配位残基的钙调蛋白变异体的变构变化的蛋白质稳定性和动力学的致病机制
IF 4 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-14 DOI: 10.1016/j.ceca.2023.102831
Christina Vallentin Holler , Nina Møller Petersson , Malene Brohus , Miska Aleksanteri Niemelä , Emil Drivsholm Iversen , Michael Toft Overgaard , Hideo Iwaï , Reinhard Wimmer

Mutations in the small, calcium-sensing, protein calmodulin cause cardiac arrhythmia and can ultimately prove lethal. Here, we report the impact of the G113R variant on the structure and dynamics of the calmodulin molecule, both in the presence and in the absence of calcium. We show that the mutation introduces minor changes into the structure of calmodulin and that it changes the thermostability and thus the degree of foldedness at human body temperature. The mutation also severely impacts the intramolecular mobility of calmodulin, especially in the apo form. Glycine 113 acts as an alpha-helical C-capping residue in both apo/ - and Ca2+/calmodulin, but its exchange to arginine has very different effects on the apo and Ca2+ forms. The majority of arrhythmogenic calmodulin variants identified affects residues in the Ca2+ coordinating loops of the two C-domain EF-Hands, causing a ‘direct impact on Ca2+ binding’. However, G113R lies outside a Ca2+ coordinating loop and acts differently and more similar to the previously characterized arrhythmogenic N53I. Therefore, we suggest that altered apo/CaM dynamics may be a novel general disease mechanism, defining low-calcium target affinity – or Ca2+ binding kinetics – critical for timely coordination of essential ion-channels in the excitation-contraction cycle.

小的钙敏感蛋白钙调蛋白的突变会导致心律失常,并最终被证明是致命的。在这里,我们报告了G113R变异对钙调素分子的结构和动力学的影响,无论是在存在还是不存在钙的情况下。我们发现突变引入了钙调素结构的微小变化,它改变了热稳定性,从而改变了人体温度下的折叠程度。突变还严重影响钙调素的分子内迁移,特别是载脂蛋白形式。甘氨酸113在apo/ -和Ca2+/钙调蛋白中都作为α -螺旋C-capping残基,但它与精氨酸的交换对apo和Ca2+形式的影响非常不同。发现的大多数致心律失常钙调蛋白变异影响两个c结构域ef - hand的Ca2+协调环中的残基,导致“直接影响Ca2+结合”。然而,G113R位于Ca2+协调环之外,其作用与先前表征的致心律失常N53I不同,更相似。因此,我们认为apo/CaM动力学的改变可能是一种新的一般疾病机制,定义了低钙靶亲和力或Ca2+结合动力学,这对于兴奋-收缩周期中必需离子通道的及时协调至关重要。
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引用次数: 0
期刊
Cell calcium
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