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In vitro and in vivo calibration of low affinity genetic Ca2+ indicators 体外和体内低亲和力遗传Ca2+指标的标定
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-08 DOI: 10.1016/j.ceca.2023.102819
Alba Delrio-lorenzo , Jonathan Rojo-ruiz, Patricia Torres-vidal, Maria Teresa Alonso, Javier García-sancho

Calcium is a universal intracellular messenger and proper Ca2+concentrations ([Ca2+]) both in the cytosol and in the lumen of cytoplasmic organelles are essential for cell functions. Ca2+ homeostasis is achieved by a delicate pump/leak balance both at the plasma membrane and at the endomembranes, and improper Ca2+ levels result in malfunction and disease. Selective intraorganellar Ca2+measurements are best achieved by using targeted genetically encoded Ca2+ indicators (GECIs) but to calibrate the luminal fluorescent signals into accurate [Ca2+] is challenging, especially in vivo, due to the difficulty to normalize and calibrate the fluorescent signal in various tissues or conditions. We report here a procedure to calibrate the ratiometric signal of GAP (GFP-Aequorin Protein) targeted to the endo-sarcoplasmic reticulum (ER/SR) into [Ca2+]ER/SR based on imaging of fluorescence after heating the tissue at 50–52 °C, since this value coincides with that obtained in the absence of Ca2+ (Rmin). Knowledge of the dynamic range (Rmax/Rmin) and the Ca2+-affinity (KD) of the indicator permits calculation of [Ca2+] by applying a simple algorithm. We have validated this procedure in vitro using several cell types (HeLa, HEK 293T and mouse astrocytes), as well as in vivo in Drosophila. Moreover, this methodology is applicable to other low Ca2+ affinity green and red GECIs.

钙是一种普遍的细胞内信使,适当的Ca2+浓度([Ca2+])在细胞质细胞器的细胞质溶胶和管腔中是细胞功能所必需的。Ca2+稳态是通过在质膜和内膜上的微妙泵/泄漏平衡来实现的,不适当的Ca2+水平会导致功能障碍和疾病。选择性胞内Ca2+测量最好通过使用靶向遗传编码的Ca2+指标(GECIs)来实现,但要将腔内荧光信号校准为准确的[Ca2+]是具有挑战性的,特别是在体内,由于难以在各种组织或条件下标准化和校准荧光信号。我们在这里报告了一种方法,在50-52°C加热组织后,根据荧光成像将靶向肌浆内网(ER/SR)的GAP (GFP-Aequorin Protein)的比率信号校准为[Ca2+]ER/SR,因为该值与缺乏Ca2+ (Rmin)时获得的值一致。该指标的动态范围(Rmax/Rmin)和Ca2+亲和力(KD)的知识允许通过应用一个简单的算法计算[Ca2+]。我们已经在体外用几种细胞类型(HeLa、HEK 293T和小鼠星形胶质细胞)以及果蝇体内验证了这一过程。此外,该方法适用于其他低Ca2+亲和力的绿色和红色geci。
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引用次数: 0
Enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction in patient-specific induced pluripotent stem cell-derived cardiomyocytes with MYH7 mutation 患者特异性诱导多能干细胞衍生的心肌细胞发生 MYH7 突变时,肌丝钙敏感性增强会加剧钙处理异常和舒张功能障碍
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-08 DOI: 10.1016/j.ceca.2023.102822
Guangli Guo , Lu Wang , Xiaowei Li , Wanrong Fu , Jinhua Cao , Jianchao Zhang , Yangyang Liu , Mengduan Liu , Mengyu Wang , Guojun Zhao , Xi Zhao , Yangfan Zhou , Shaohui Niu , Gangqiong Liu , Yanzhou Zhang , Jianzeng Dong , Hailong Tao , Xiaoyan Zhao

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is frequently caused by mutations in the β-cardiac myosin heavy chain gene (MYH7). Abnormal calcium handling and diastolic dysfunction are archetypical features of HCM caused by MYH7 gene mutations. However, the mechanism of how MYH7 mutations leads to these features remains unclear, which inhibits the development of effective therapies. Initially, cardiomyocytes were generated from induced pluripotent stem cells from an eight-year-old girl diagnosed with HCM carrying a MYH7(C.1063 G>A) heterozygous mutation(mutant-iPSC-CMs) and mutation-corrected isogenic iPSCs(control-iPSC-CMs) in the present study. Next, we compared phenotype of mutant-iPSC-CMs to that of control-iPSC-CMs, by assessing their morphology, hypertrophy-related genes expression, calcium handling, diastolic function and myofilament calcium sensitivity at days 15 and 40 respectively. Finally, to better understand increased myofilament Ca2+ sensitivity as a central mechanism of central pathogenicity in HCM, inhibition of calcium sensitivity with mavacamten can improveed cardiomyocyte hypertrophy. Mutant-iPSC-CMs exhibited enlarged areas, increased sarcomere disarray, enhanced expression of hypertrophy-related genes proteins, abnormal calcium handling, diastolic dysfunction and increased myofilament calcium sensitivity at day 40, but only significant increase in calcium sensitivity and mild diastolic dysfunction at day 15. Increased calcium sensitivity by levosimendan aggravates cardiomyocyte hypertrophy phenotypes such as expression of hypertrophy-related genes, abnormal calcium handling and diastolic dysfunction, while inhibition of calcium sensitivity significantly improves cardiomyocyte hypertrophy phenotypes in mutant-iPSC-CMs, suggesting increased myofilament calcium sensitivity is the primary mechanisms for MYH7 mutations pathogenesis. Our studies have uncovered a pathogenic mechanism of HCM caused by MYH7 gene mutations through which enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction. Correction of the myofilament calcium sensitivity was found to be an effective method for treating the development of HCM phenotype in vitro.

肥厚性心肌病(HCM)是最常见的遗传性心脏病,通常由β-心肌肌球蛋白重链基因(MYH7)突变引起。钙处理异常和舒张功能障碍是由MYH7基因突变引起的HCM的典型特征。然而,MYH7突变如何导致这些特征的机制尚不清楚,这抑制了有效治疗方法的发展。最初,从一名被诊断为HCM的8岁女孩的诱导多能干细胞中产生心肌细胞,该女孩携带MYH7(C.1063)基因G>A)杂合突变(突变- ipsc - cms)和突变校正的等基因ipsc(对照- ipsc - cms)。接下来,我们分别在第15天和第40天通过评估形态学、肥大相关基因表达、钙处理、舒张功能和肌丝钙敏感性来比较突变型ipsc - cms与对照ipsc - cms的表型。最后,为了更好地理解肌丝Ca2+敏感性增加作为HCM中心致病性的中心机制,用马伐卡坦抑制钙敏感性可以改善心肌细胞肥厚。突变型ipsc - cms在第40天表现出面积增大、肌节紊乱增加、肥厚相关基因蛋白表达增强、钙处理异常、舒张功能障碍和肌丝钙敏感性增加,但在第15天仅出现钙敏感性显著增加和轻度舒张功能障碍。左西孟丹增加钙敏感性加重心肌细胞肥厚表型,如肥厚相关基因的表达、钙处理异常和舒张功能障碍,而抑制钙敏感性可显著改善突变型ipsc - cms中心肌细胞肥厚表型,提示肌丝钙敏感性增加是MYH7突变发病的主要机制。我们的研究揭示了MYH7基因突变引起HCM的致病机制,通过MYH7基因突变,肌丝钙敏感性增强加重了钙处理异常和舒张功能障碍。纠正肌丝钙敏感性是体外治疗HCM表型发展的有效方法。
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引用次数: 0
Transcriptional, biochemical, and immunohistochemical analyses of CaMKKβ/2 splice variants that co-localize with CaMKIV in spermatids 精子中CaMKKβ/2剪接变体与CaMKIV共定位的转录、生化和免疫组织化学分析
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-08 DOI: 10.1016/j.ceca.2023.102820
Satomi Ohtsuka , Yumi Miyai , Hiroyuki Mima , Masaki Magari , Yoichi Chiba , Futoshi Suizu , Hiroyuki Sakagami , Masaki Ueno , Hiroshi Tokumitsu

Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) phosphorylates and activates downstream protein kinases, including CaMKI, CaMKIV, PKB/Akt, and AMPK; thus, regulates various Ca2+-dependent physiological and pathophysiological pathways. Further, CaMKKβ/2 in mammalian species comprises multiple alternatively spliced variants; however, their functional differences or redundancy remain unclear. In this study, we aimed to characterize mouse CaMKKβ/2 splice variants (CaMKKβ-3 and β-3x). RT-PCR analyses revealed that mouse CaMKKβ-1, consisting of 17 exons, was predominantly expressed in the brain; whereas, mouse CaMKKβ-3 and β-3x, lacking exon 16 and exons 14/16, respectively, were primarily expressed in peripheral tissues. At the protein level, the CaMKKβ-3 or β-3x variants showed high expression levels in mouse cerebrum and testes. This was consistent with the localization of CaMKKβ-3/-3x in spermatids in seminiferous tubules, but not the localization of CaMKKβ-1. We also observed the co-localization of CaMKKβ-3/-3x with a target kinase, CaMKIV, in elongating spermatids. Biochemical characterization further revealed that CaMKKβ-3 exhibited Ca2+/CaM-induced kinase activity similar to CaMKKβ-1. Conversely, we noted that CaMKKβ-3x impaired Ca2+/CaM-binding ability, but exhibited significantly weak autonomous activity (approximately 500-fold lower than CaMKKβ-1 or β-3) due to the absence of C-terminal of the catalytic domain and a putative residue (Ile478) responsible for the kinase autoinhibition. Nevertheless, CaMKKβ-3x showed the ability to phosphorylate downstream kinases, including CaMKIα, CaMKIV, and AMPKα in transfected cells comparable to CaMKKβ-1 and β-3. Collectively, CaMKKβ-3/-3x were identified as functionally active and could be bona fide CaMKIV-kinases in testes involved in the activation of the CaMKIV cascade in spermatids, resulting in the regulation of spermiogenesis.

Ca2+/钙调素依赖性蛋白激酶(CaMKK)磷酸化并激活下游蛋白激酶,包括CaMKI、CaMKIV、PKB/Akt和AMPK;因此,调节各种Ca2+依赖的生理和病理生理途径。此外,哺乳动物物种中的CaMKKβ/2包括多个可选剪接变体;然而,它们的功能差异或冗余性尚不清楚。在这项研究中,我们旨在表征小鼠CaMKKβ/2剪接变体(CaMKKβ-3和β-3x)。RT-PCR分析显示,小鼠CaMKKβ-1由17个外显子组成,主要在大脑中表达;而小鼠CaMKKβ-3和β-3x分别缺失外显子16和14/16,主要在外周组织中表达。在蛋白水平上,CaMKKβ-3或β-3x变体在小鼠大脑和睾丸中表现出高表达水平。这与CaMKKβ-3/-3x在精细胞精管中的定位一致,而与CaMKKβ-1的定位不一致。我们还观察到CaMKKβ-3/-3x与靶激酶CaMKIV在伸长精子中的共定位。生化表征进一步表明,CaMKKβ-3表现出与CaMKKβ-1相似的Ca2+/ cam诱导的激酶活性。相反,我们注意到CaMKKβ-3x损害了Ca2+/ cam的结合能力,但由于缺乏催化结构域的c末端和负责激酶自抑制的推定残基(Ile478), CaMKKβ-3x表现出明显弱的自主活性(比CaMKKβ-1或β-3低约500倍)。然而,与CaMKKβ-1和β-3相比,CaMKKβ-3x在转染细胞中表现出磷酸化下游激酶的能力,包括camkk α、CaMKIV和AMPKα。总的来说,CaMKKβ-3/-3x被鉴定为具有功能活性,并且可能是睾丸中真正的CaMKIV激酶,参与激活精子中CaMKIV级联反应,从而调节精子发生。
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引用次数: 0
Subcellular localization and transcriptional regulation of brain ryanodine receptors. Functional implications 脑ryanodine受体的亚细胞定位和转录调控。功能含义。
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-04 DOI: 10.1016/j.ceca.2023.102821
Rodrigo Torres , Cecilia Hidalgo

Ryanodine receptors (RyR) are intracellular Ca2+ channels localized in the endoplasmic reticulum, where they act as critical mediators of Ca2+-induced Ca2+ calcium release (CICR). In the brain, mammals express in both neurons, and non-neuronal cells, a combination of the three RyR-isoforms (RyR1–3). Pharmacological approaches, which do not distinguish between isoforms, have indicated that RyR-isoforms contribute to brain function. However, isoform-specific manipulations have revealed that RyR-isoforms display different subcellular localizations and are differentially associated with neuronal function. These findings raise the need to understand RyR-isoform specific transcriptional regulation, as this knowledge will help to elucidate the causes of neuronal dysfunction for a growing list of brain disorders that show altered RyR channel expression and function.

Ryanodine受体(RyR)是定位于内质网的细胞内Ca2+通道,在内质网中它们充当Ca2+诱导的Ca2+钙释放(CICR)的关键介质。在大脑中,哺乳动物在神经元和非神经元细胞中表达三种RyR亚型(RyR1-3)的组合。药理学方法不区分同种型,表明RyR同种型有助于大脑功能。然而,同种型特异性操作显示,RyR同种型表现出不同的亚细胞定位,并与神经元功能有不同的相关性。这些发现提出了理解RyR亚型特异性转录调控的必要性,因为这些知识将有助于阐明越来越多的大脑疾病的神经元功能障碍的原因,这些疾病显示出RyR通道表达和功能的改变。
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引用次数: 0
Sodium homeostasis and signalling: The core and the hub of astrocyte function 钠稳态和信号传导:星形胶质细胞功能的核心和枢纽
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-04 DOI: 10.1016/j.ceca.2023.102817
Christine R. Rose , Alexej Verkhratsky

Neuronal activity and neurochemical stimulation trigger spatio-temporal changes in the cytoplasmic concentration of Na+ ions in astrocytes. These changes constitute the substrate for Na+ signalling and are fundamental for astrocytic excitability. Astrocytic Na+ signals are generated by Na+ influx through neurotransmitter transporters, with primary contribution of glutamate transporters, and through cationic channels; whereas recovery from Na+ transients is mediated mainly by the plasmalemmal Na+/K+ ATPase. Astrocytic Na+ signals regulate the activity of plasmalemmal transporters critical for homeostatic function of astrocytes, thus providing real-time coordination between neuronal activity and astrocytic support.

神经元活动和神经化学刺激引发星形胶质细胞胞质Na+离子浓度的时空变化。这些变化构成Na+信号传导的底物,是星形细胞兴奋性的基础。星形胶质细胞Na+信号是由Na+通过神经递质(主要是谷氨酸转运体)内流并通过阳离子通道产生的;而Na+瞬态的恢复主要是由细胞质Na+/K+ atp酶介导的。星形胶质细胞Na+信号调节对星形胶质细胞稳态功能至关重要的质浆转运蛋白的活性,从而在神经元活动和星形胶质细胞支持之间提供实时协调。
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引用次数: 0
Neuronal and astrocyte NCX isoform/splice variants: How do they participate in Na+ and Ca2+ signalling? 神经元和星形细胞NCX异构体/剪接变体:它们如何参与Na+和Ca2+信号传导?
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-10-24 DOI: 10.1016/j.ceca.2023.102818
Daniel Khananshvili

NCX1, NCX2, and NCX3 gene isoforms and their splice variants are characteristically expressed in different regions of the brain. The tissue-specific splice variants of NCX1–3 isoforms show specific expression profiles in neurons and astrocytes, whereas the relevant NCX isoform/splice variants exhibit diverse allosteric modes of Na+- and Ca2+-dependent regulation. In general, overexpression of NCX1–3 genes leads to neuroprotective effects, whereas their ablation gains the opposite results. At this end, the partial contributions of NCX isoform/splice variants to neuroprotective effects remain unresolved. The glutamate-dependent Na+ entry generates Na+ transients (in response to neuronal cell activities), whereas the Na+-driven Ca2+ entry (through the reverse NCX mode) raises Ca2+ transients. This special mode of signal coupling translates Na+ transients into the Ca2+ signals while being a part of synaptic neurotransmission. This mechanism is of general interest since disease-related conditions (ischemia, metabolic stress, and stroke among many others) trigger Na+ and Ca2+ overload with deadly outcomes of downstream apoptosis and excitotoxicity. The recently discovered mechanisms of NCX allosteric regulation indicate that some NCX variants might play a critical role in the dynamic coupling of Na+-driven Ca2+ entry. In contrast, the others are less important or even could be dangerous under altered conditions (e.g., metabolic stress). This working hypothesis can be tested by applying advanced experimental approaches and highly focused computational simulations. This may allow the development of structure-based blockers/activators that can selectively modulate predefined NCX variants to lessen the life-threatening outcomes of excitotoxicity, ischemia, apoptosis, metabolic deprivation, brain injury, and stroke.

NCX1、NCX2和NCX3基因异构体及其剪接变体在大脑的不同区域具有特征性表达。NCX1-3异构体的组织特异性剪接变体在神经元和星形胶质细胞中表现出特异性表达谱,而相关的NCX异构体/剪接变体表现出Na+-和Ca2+依赖性调节的不同变构模式。一般来说,NCX1-3基因的过表达会导致神经保护作用,而其消融则会获得相反的结果。在这方面,NCX异构体/剪接变体对神经保护作用的部分贡献仍未得到解决。谷氨酸依赖的Na+进入产生Na+瞬态(响应神经元细胞活动),而Na+驱动的Ca2+进入(通过反向NCX模式)提高Ca2+瞬态。这种特殊的信号耦合模式将Na+瞬态转化为Ca2+信号,同时也是突触神经传递的一部分。这种机制是普遍感兴趣的,因为疾病相关的条件(缺血、代谢应激和中风等)触发Na+和Ca2+超载,导致下游细胞凋亡和兴奋性毒性的致命结果。最近发现的NCX变构调节机制表明,一些NCX变异可能在Na+驱动的Ca2+进入的动态耦合中起关键作用。相比之下,其他的不那么重要,甚至在改变的条件下可能是危险的(例如,代谢压力)。这个工作假设可以通过应用先进的实验方法和高度集中的计算模拟来验证。这可能允许开发基于结构的阻断剂/激活剂,可以选择性地调节预定义的NCX变异,以减轻兴奋毒性、缺血、凋亡、代谢剥夺、脑损伤和中风等危及生命的结果。
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引用次数: 0
TPC2 gating: Trying to break the enigma code TPC2门控:试图破解谜码
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-10-18 DOI: 10.1016/j.ceca.2023.102815
Francesco Moccia , Anthony J. Morgan
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引用次数: 0
Calcium transport and sensing in TRPC channels – New insights into a complex feedback regulation 钙在TRPC通道中的转运和传感-对复杂反馈调节的新见解。
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-10-18 DOI: 10.1016/j.ceca.2023.102816
Jasmin Baron, Klaus Groschner, Oleksandra Tiapko

Canonical TRP (TRPC) channels are a still enigmatic family of signaling molecules with multimodal sensing features. These channels enable Ca2+ influx through the plasma membrane to control a diverse range of cellular functions. Based on both regulatory- and recently uncovered structural features, TRPC channels are considered to coordinate Ca2+ and other divalent cations not only within the permeation path but also at additional sensory sites. Analysis of TRPC structures by cryo-EM identified multiple regulatory ion binding pockets. With this review, we aim at an overview and a critical discussion of the current concepts of divalent sensing by TRPC channels.

典型TRP(TRPC)通道是一个仍然神秘的具有多峰传感特征的信号分子家族。这些通道使Ca2+能够通过质膜流入,以控制各种细胞功能。基于调节和最近未发现的结构特征,TRPC通道被认为不仅在渗透路径内,而且在额外的感觉位点协调Ca2+和其他二价阳离子。通过冷冻电镜对TRPC结构的分析确定了多个调节性离子结合口袋。通过这篇综述,我们旨在对TRPC通道二价传感的当前概念进行概述和批判性讨论。
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引用次数: 0
Commentary: Untangling the structural and enzymatic roles of CaMKII at the synapse 解说:解开CaMKII在突触中的结构和酶促作用。
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-10-05 DOI: 10.1016/j.ceca.2023.102813
Daniela Anderson , A.J. Robison
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引用次数: 0
Structural insights into the TRPV4-RhoA complex offer clues to solve the puzzle of TRPV4 channelopathies 对TRPV4-RhoA复合体的结构见解为解决TRPV4通道病之谜提供了线索。
IF 4 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-10-04 DOI: 10.1016/j.ceca.2023.102814
Xueming Hu , Hongzhen Hu
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引用次数: 0
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Cell calcium
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