Cell calcium最新文献

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Mitochondrial Ca2+ uniporter b (MCUb) regulates neuronal Ca2+ dynamics and resistance to ischemic stroke 线粒体Ca2+单转运蛋白b （MCUb）调节神经元Ca2+动力学和缺血性卒中的抵抗

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-02-27 DOI: 10.1016/j.ceca.2025.103013

Tam Nguyen , Zhihong Lin , Nirav Dhanesha , Rakesh B. Patel , Mallorie Lane , Grant C. Walters , Leonid P. Shutov , Stefan Strack , Anil K. Chauhan , Yuriy M. Usachev

Mitochondrial Ca²⁺ transport regulates many neuronal functions including synaptic transmission, ATP production, gene expression and neuronal survival. The mitochondrial Ca²⁺ uniporter (MCU) is the core molecular component of the mitochondrial Ca²⁺ uptake complex in the inner mitochondrial membrane. MCUb is a paralog of MCU that negatively regulates mitochondrial Ca²⁺ uptake in the heart and the cells of the immune system. However, the function of MCUb in the brain is largely unknown. Here, we report that MCUb knockout (KO) led to enhanced mitochondrial Ca²⁺ uptake in cortical neurons. By simultaneously monitoring changes in cytosolic and mitochondrial Ca²⁺ concentrations, [Ca²⁺]_cyt and [Ca²⁺]_mt, respectively, we also found that MCUb KO reduced the [Ca²⁺]_cyt threshold required to induce mitochondrial uptake in cortical neurons during electrical stimulation. Exposure of cortical neurons to toxic concentrations of glutamate led to a collapse of mitochondrial membrane potential (ΔΨ_mt) and [Ca²⁺]_cyt deregulation, and MCUb deletion accelerated the development of both events. Furthermore, using the middle cerebral artery occlusion (MCAO) as a model of transient ischemic stroke in mice, we found that MCUb KO significantly increased MCAO-induced brain damage in male, but not female mice. These results suggest that MCUb regulates neuronal Ca²⁺ dynamics and excitotoxicity and reveal a sex-dependent role of MCUb in controlling resistance to brain damage following ischemic stroke.

线粒体Ca2+转运调节许多神经元功能，包括突触传递、ATP产生、基因表达和神经元存活。线粒体Ca2+单转运蛋白（MCU）是线粒体内膜Ca2+摄取复合物的核心分子成分。MCUb是MCU的一种类似物，可负调控心脏和免疫系统细胞中的线粒体Ca2+摄取。然而，MCUb在大脑中的功能在很大程度上是未知的。在这里，我们报告MCUb敲除（KO）导致皮质神经元线粒体Ca2+摄取增强。通过同时监测细胞质和线粒体Ca2+浓度，[Ca2+]cyt和[Ca2+]mt的变化，我们还发现MCUb KO降低了在电刺激期间诱导皮质神经元线粒体摄取所需的[Ca2+]cyt阈值。皮质神经元暴露于有毒浓度的谷氨酸导致线粒体膜电位崩溃（ΔΨmt）和[Ca2+]细胞解除管制，而MCUb缺失加速了这两种事件的发展。此外，使用大脑中动脉闭塞（MCAO）作为小鼠短暂性缺血性卒中模型，我们发现MCUb KO显著增加了MCAO诱导的雄性小鼠脑损伤，而雌性小鼠没有。这些结果表明，MCUb调节神经元Ca2+动力学和兴奋毒性，并揭示了MCUb在控制缺血性卒中后脑损伤抵抗中的性别依赖作用。

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引用次数: 0

Changing of the guards while steering a familiar course 在熟悉的路线上换岗

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-02-15 DOI: 10.1016/j.ceca.2025.103002

Barbara A. Niemeyer , David I. Yule

引用次数: 0

Rapid quantification of intracellular calcium stores reveals effects of membrane micropeptides on SERCA function 细胞内钙储存的快速定量揭示了膜微肽对SERCA功能的影响

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-02-07 DOI: 10.1016/j.ceca.2025.103000

Jacob D. Cunningham, Taylor A. Phillips, Jaroslava Seflova, Ellen E. Cho, Seth L. Robia

To determine how regulation of the sarco(endo)plasmic reticulum calcium ATPase (SERCA) affects the Ca²⁺ content of the endoplasmic reticulum (ER), we developed a ratiometric ER-localized Ca²⁺ indicator to rapidly quantify Ca²⁺ stores and assess SERCA function in live cells. This assay enables screening of membrane micropeptides and small molecules that modulate SERCA and Na⁺/K⁺-ATPase activity and may facilitate development of therapies that target cellular Ca²⁺ handling. Of the micropeptides tested, phospholamban (PLB) had the greatest degree of inhibition of SERCA, as measured by a decrease in ER Ca²⁺ content compared to control. Sarcolipin (SLN), endoregulin (ELN), and another-regulin (ALN) also decreased ER Ca²⁺ content, though less potently than PLB. We also investigated micropeptides that have been shown to have a positive effect on ER Ca²⁺ uptake. Dwarf open reading frame (DWORF), a positive modulator of SERCA activity, and phospholemman (PLM), an inhibitor of the Na⁺/K⁺-ATPase, both increased ER Ca²⁺ content compared to control. A superinhibitory variant of PLM, R70C, further increased ER Ca²⁺ load compared to wild type PLM. Overall, our findings indicate that the inhibitory potency of micropeptides is governed by their relative binding affinities to SERCA. This allows for finely tuned modulation of Ca²⁺ handling in different tissues based on differential expressions of micropeptide species. Understanding the contribution of each micropeptide to SERCA regulation may reveal novel strategies for therapeutic intervention in conditions where calcium dysregulation plays a role, such as heart disease, vascular disease, or neurodegenerative disorders.

为了确定sarco（内do）质网钙atp酶（SERCA）的调节如何影响内质网（ER）的Ca2+含量，我们开发了一种比例内质网定位的Ca2+指标，以快速量化Ca2+储存并评估活细胞中的SERCA功能。该分析能够筛选调节SERCA和Na+/K+- atp酶活性的膜微肽和小分子，并可能促进针对细胞Ca2+处理的治疗的发展。在所测试的微肽中，磷蛋白（PLB）对SERCA的抑制程度最大，与对照相比，其ER Ca2+含量降低。肌磷脂（SLN）、内调节蛋白（ELN）和另一调节蛋白（ALN）也能降低内质网Ca2+含量，但效果不如PLB。我们还研究了已被证明对ER Ca2+摄取有积极影响的微肽。与对照组相比，SERCA活性的正调节因子Dwarf open reading frame （DWORF）和Na+/K+- atp酶抑制剂phospholemman （PLM）均增加了ER Ca2+含量。与野生型PLM相比，PLM的超抑制变体R70C进一步增加了ER Ca2+负荷。总的来说，我们的研究结果表明，微肽的抑制效力是由它们与SERCA的相对结合亲和力决定的。这允许精细调节Ca2+处理在不同组织中基于微肽物种的差异表达。了解每种微肽对SERCA调节的作用，可能会为钙失调起作用的疾病（如心脏病、血管疾病或神经退行性疾病）的治疗干预提供新的策略。

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Shocking insights for neurovascular coupling: Electrical signals ignite calcium dynamics in brain capillaries 神经血管耦合的惊人见解：电信号点燃脑毛细血管中的钙动力学。

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-02-01 DOI: 10.1016/j.ceca.2025.103001

Boris Lavanderos , Maria Paz Saldias , Scott Earley

Brain capillaries contribute to neurovascular coupling (NVC) by sensing neural activity and coordinating upstream arteriole dilation. However, the mechanisms underlying conducted vasodilation remain incompletely understood. Recent findings (PNAS, 2024) identify a novel process, “electrocalcium coupling,” in which hyperpolarizing signals from K⁺ channels drive long-range Ca²⁺ signaling in capillaries, revealing new insights into the integration of vasodilatory signals in the brain.

脑毛细血管通过感知神经活动和协调上游小动脉扩张参与神经血管耦合（NVC）。然而，传导血管舒张的机制仍然不完全清楚。最近的发现（PNAS, 2024）确定了一个新的过程，“电钙耦合”，其中来自K+通道的超极化信号驱动毛细血管中的远程Ca 2 +信号，揭示了大脑中血管舒张信号整合的新见解。

引用次数: 0

You better keep an eye on your contacts 你最好看好你的隐形眼镜。

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-01-22 DOI: 10.1016/j.ceca.2025.102999

Tamas Balla, Gergo Gulyas

Membrane contact sites (MCS) are specialized compartments found in all eukaryotic cells that are formed between membranes of different organelles that are in close proximity. MCS have important functions as they are sites of efficient transfer of molecules between neighboring organelles. Two recent articles have used the splitFAST system to mark and follow the dynamics of membrane contact sites and used the method to highlight the importance of MCS between the endoplasmic reticulum (ER) and lipid droplets in metabolic adaptation and MCS between the ER and mitochondria in Ca²⁺ signal propagation.

膜接触位点（MCS）是在所有真核细胞中发现的特殊隔室，它形成于靠近的不同细胞器的膜之间。MCS具有重要的功能，因为它们是分子在邻近细胞器之间有效转移的场所。最近的两篇文章使用splitFAST系统标记和跟踪膜接触位点的动态，并使用该方法强调内质网（ER）和脂滴之间的MCS在代谢适应中的重要性，内质网和线粒体之间的MCS在Ca2+信号传播中的重要性。

引用次数: 0

Commentary to An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease (Zhao et al., EMBO Journal 2024) and A gain-of-function mutation in the Ca2+ channel ORAI1 causes Stormorken syndrome with tubular aggregates in mice (Pérez-Guàrdia et al., Cells 2024) Orai1功能获得性小管聚集性肌病小鼠模型显示了人类疾病的关键特征（Zhao等人，EMBO Journal 2024）和Ca2+通道Orai1的功能获得性突变导致小鼠具有小管聚集性Stormorken综合征（Pérez-Guàrdia等人，Cells 2024）。

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-01-21 DOI: 10.1016/j.ceca.2025.102998

Johann Böhm

引用次数: 0

Ionic signalling (beyond calcium) in the nervous system: Physiology and pathophysiology 神经系统中的离子信号（除钙外）：生理学和病理生理学。

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-01-01 DOI: 10.1016/j.ceca.2024.102984

Verena Untiet , Chritsine R. Rose , Maiken Nedergaard , Alexei Verkhratsky

引用次数: 0

STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis 刺激IRE1：储存操作的Ca2+进入如何与内质网蛋白酶平衡相交。

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-01-01 DOI: 10.1016/j.ceca.2024.102980

Maria Livia Sassano , Robbe Van Gorp , Geert Bultynck , Patrizia Agostinis

The endoplasmic reticulum (ER) controls intracellular Ca²⁺ dynamics. Depletion of ER Ca²⁺ stores results in short-term activation of store-operated Ca²⁺ entry (SOCE) via STIM1/Orai1 at ER-plasma membrane (ER-PM) contact sites (MCSs) and the long-term activation of the unfolded protein response (UPR), securing ER proteostasis. Recent work by Carreras-Sureda and colleagues describes a bidirectional control between IRE1 and STIM1 within the ER lumen that regulates ER-PM contact assembly and SOCE to sustain T-cell activation and myoblast differentiation.

内质网（ER）控制着细胞内 Ca2+ 的动态变化。ER Ca2+ 储存的耗竭会导致通过ER-质膜（ER-PM）接触点（MCSs）上的 STIM1/Orai1 短期激活储存操作的 Ca2+ 进入（SOCE），并长期激活未折叠蛋白反应（UPR），从而确保ER的蛋白稳态。Carreras-Sureda 及其同事最近的研究描述了ER腔内IRE1和STIM1之间的双向控制，这种控制调节ER-PM接触组装和SOCE，以维持T细胞活化和成肌细胞分化。

引用次数: 0

A role for lysosomal calcium channels in mitigating mitochondrial damage and oxidative stress 溶酶体钙通道在减轻线粒体损伤和氧化应激中的作用。

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-01-01 DOI: 10.1016/j.ceca.2024.102986

Leandro C. Clementino , Andrew P. Thomas , Emily M. Rocha , Sabine Hilfiker

Elevated free fatty acids and oxidative stress may function as pathogenic factors in endothelial dysfunction that is associated with various cardiovascular complications. In recent work, Feng and colleagues report that activation of a lysosomal Ca²⁺ channel may be a viable option to alleviate oxidative damage by boosting lysosome biogenesis and mitophagy.

游离脂肪酸升高和氧化应激可能是与各种心血管并发症相关的内皮功能障碍的致病因素。在最近的研究中，Feng和他的同事报告说，激活溶酶体Ca2+通道可能是一种可行的选择，可以通过促进溶酶体的生物发生和线粒体自噬来减轻氧化损伤。

引用次数: 0

TPC2 controls MITF expression and metastasis in melanoma TPC2控制黑色素瘤中MITF的表达和转移。

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-01-01 DOI: 10.1016/j.ceca.2024.102989

M. Raza Zaidi , Jonathan Soboloff

Recent findings by Abrahamian et al. (2024) provides new insights into the relationship between Two Pore Channel 2 (TPC2) activity and the development and progression of melanoma. Melanocyte inducing transcription factor (MITF) is a critical regulator of both melanocyte and melanoma behavior. Abrahamian et al. (2024) show that MITF-high melanoma requires BOTH Rab7a and TPC2 for proliferation, invasion and metastasis. They further identify Wnt signaling as the mediator of this phenomenon; Rab7a induces TPC2 activity in lysosomes and melanosomes, which regulates GSK-3β stability, thereby determining whether β-catenin escapes degradation and translocates to the nucleus to transcribe the MITF gene. These observations provide new insights into the relationship between ion channel function, lysosomal/melanosomal activity and control for oncogenesis and disease progression in melanoma.

Abrahamian等人（2024）的最新发现为双孔通道2 （Two Pore Channel 2, TPC2）活性与黑色素瘤的发生和发展之间的关系提供了新的见解。黑素细胞诱导转录因子（MITF）是黑素细胞和黑色素瘤行为的关键调节因子。Abrahamian等（2024）发现mitf高的黑色素瘤的增殖、侵袭和转移都需要Rab7a和TPC2。他们进一步确定Wnt信号是这一现象的中介；Rab7a诱导溶酶体和黑素小体中的TPC2活性，从而调节GSK-3β的稳定性，从而决定β-catenin是否逃脱降解并易位到细胞核中转录MITF基因。这些观察结果为离子通道功能、溶酶体/黑素体活性与黑色素瘤发生和疾病进展的控制之间的关系提供了新的见解。

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