Cell calcium最新文献

{"title":"MICU1 attenuates neuronal apoptosis after subarachnoid hemorrhage by inhibiting mitochondrial calcium overload and damage","authors":"Jie Wang ,&nbsp;Yue Cui ,&nbsp;Peng-Fei Ding ,&nbsp;Jia-Tong Zhang ,&nbsp;Xun-Zhi Liu ,&nbsp;Sen Gao ,&nbsp;Xiang-Xin Chen ,&nbsp;Zheng Peng ,&nbsp;Xiao-Jian Li ,&nbsp;Ling-Yun Wu ,&nbsp;Yong-Yue Gao ,&nbsp;Chun-Hua Hang ,&nbsp;Wei Li","doi":"10.1016/j.ceca.2025.103080","DOIUrl":"10.1016/j.ceca.2025.103080","url":null,"abstract":"<div><h3>Background</h3><div>Subarachnoid hemorrhage (SAH) is a severe neurological emergency associated with substantial morbidity and mortality. Research into the mechanisms underlying neuronal injury following SAH has identified early brain injury (EBI) as a critical factor influencing clinical outcomes. Among the various pathological processes involved in EBI, calcium overload remains relatively understudied yet plays a pivotal role in neuronal damage. Excessive accumulation of calcium within mitochondria can initiate apoptotic and autophagic pathways, contributing to cell death. Mitochondrial calcium uptake 1 (MICU1), a regulatory protein located on the inner mitochondrial membrane, functions to modulate mitochondrial calcium ions by inhibiting calcium influx under conditions of low intracellular calcium concentration.</div></div><div><h3>Methods</h3><div>Mitochondria were extracted from the cerebrospinal fluid (CSF) of patients with SAH to evaluate the extent of mitochondrial damage. In vivo and in vitro SAH models were employed to assess mitochondrial damage and dynamic changes in both mitochondrial and cytosolic calcium levels. The interaction between MICU1 and mitochondria was further examined. To investigate the functional role of MICU1, lentivirus vectors were used to upregulate MICU1 expression, while siRNA was applied to knock down its expression in Neuron-2a (N2a) cells. Following hemoglobin (Hb) stimulation, mitochondrial damage and apoptosis were systematically evaluated.</div></div><div><h3>Results</h3><div>Analysis of CSF from SAH patients revealed decreased MICU1 expression and aggravated mitochondrial damage. Hb stimulation of primary neurons and N2a cells led to reduced MICU1 expression and mitochondrial calcium overload, which mediated mitochondrial damage and promoted the progression of neuronal apoptosis. Following upregulation of MICU1 expression in N2a cells, the cells exhibited enhanced tolerance to Hb-induced calcium overload, resulting in a significant reduction in mitochondrial damage. This protective effect was attenuated by MICU1 siRNA treatment. Moreover, MICU1 overexpression alleviated Hb-induced apoptosis in N2a cells, whereas siRNA-mediated knockdown of MICU1 exacerbated apoptotic responses.</div></div><div><h3>Conclusion</h3><div>Mitochondrial calcium overload in neurons following SAH contributes to the development of EBI and neuronal damage. MICU1 exerts a neuroprotective role by mitigating mitochondrial calcium overload, thereby reducing mitochondrial damage and neuronal apoptosis.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103080"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silencing CALB1 enhances prostate cancer radiosensitivity via calcium-mediated mitochondrial dysfunction and cellular senescence","authors":"Chen Gong ,&nbsp;Senmao Li ,&nbsp;Ye An ,&nbsp;Chadanfeng Yang ,&nbsp;Zhiyong Tan ,&nbsp;Wujie Chen ,&nbsp;Dihao Lv ,&nbsp;Haichao Wu ,&nbsp;Haifeng Wang ,&nbsp;Shi Fu ,&nbsp;Haihao Li ,&nbsp;Yanjie Kong ,&nbsp;Yinglong Huang ,&nbsp;Mingxia Ding","doi":"10.1016/j.ceca.2025.103071","DOIUrl":"10.1016/j.ceca.2025.103071","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer remains a leading cause of cancer-related deaths in men, with radioresistance limiting treatment efficacy. This study investigates the role of Calbindin 1 (CALB1), a calcium-binding protein regulated by miR-186–5p, in prostate cancer progression and radiation response.</div></div><div><h3>Methods</h3><div>CALB1 expression was analyzed using GEO and TCGA datasets, and the regulatory relationship with miR-186–5p was validated. Functional studies including CALB1 knockdown, calcium chelation, and mitochondrial rescue interventions were conducted in prostate cancer cells, spheroids, and xenograft models, assessing proliferation, senescence, calcium homeostasis, and radiation response.</div></div><div><h3>Results</h3><div>We identified CALB1 as a target of downregulated miR-186–5p in prostate cancer. CALB1 silencing inhibited prostate cancer growth by inducing cellular senescence through calcium dysregulation, mitochondrial dysfunction, and oxidative stress. CALB1 depletion significantly enhanced radiosensitivity both in vitro and in vivo, with calcium chelation or mitochondrial interventions partially rescuing these effects.</div></div><div><h3>Conclusions</h3><div>CALB1 regulates prostate cancer progression and radiation response by maintaining calcium homeostasis. Its depletion triggers calcium overload and mitochondrial dysfunction, enhancing radiation sensitivity and identifying CALB1 as a potential therapeutic target.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103071"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological calcium influx through amyloid beta pores disrupts synaptic function","authors":"Temitope Adeoye,&nbsp;Ghanim Ullah","doi":"10.1016/j.ceca.2025.103083","DOIUrl":"10.1016/j.ceca.2025.103083","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by profound disruption of synaptic function, with mounting evidence suggesting that amyloid-β (Aβ) oligomers disrupt calcium (Ca²⁺) homeostasis through membrane pore formation. While these pores are known to alter intracellular Ca²⁺ dynamics, their immediate impact on synaptic transmission and potential interaction with Familial AD (FAD)-associated endoplasmic reticulum (ER) dysfunction remains unclear. Here, we extend our previously developed model of presynaptic Ca²⁺ dynamics to examine how Aβ pores alter exocytosis and how such disruptions may manifest in the presence of FAD-associated ER dysfunction. Our model reveals that Aβ pores fundamentally alter both the timing and strength of neurotransmitter release. Unexpectedly, the impact of pores on synaptic function depends critically on their pattern of activity, where continuous pore activity leads to synaptic hyperactivation, while brief periods of intense pore activity trigger lasting hypoactivation at short timescales. These effects manifest most strongly in synapses with low and intermediate release probabilities, highlighting the established selective vulnerability of such synaptic configurations. We find that Aβ pores and FAD-driven ER Ca²⁺ dysregulation form an integrated pathological unit through bidirectional coupling of their respective Ca²⁺ microdomains to create complex patterns of disruptions. This coupling creates a feedback loop that produces an additive effect on neurotransmitter release during brief stimulations, but non-additive effects during sustained activity that promotes a shift towards asynchronous release. Surprisingly, our simulations predict that extended pore activity does not worsen indefinitely but only produces a modest additional disruption beyond initial pore formation that is likely determined by the intrinsic properties of the synapse. These findings indicate that early synaptic dysfunction in AD may arise from subtle perturbations in the temporal coordination of release rather than gross Ca²⁺ dysregulation, providing new mechanistic insights into the progressive nature of Aβ-driven synaptic failure in AD.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103083"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CPVT1 point mutations in RyR2 S5 and S6 segments and their Ca2+ signaling consequence","authors":"Xiao-hua Zhang ,&nbsp;Grace Ellen Donch ,&nbsp;Naohiro Yamaguchi ,&nbsp;Martin Morad","doi":"10.1016/j.ceca.2025.103081","DOIUrl":"10.1016/j.ceca.2025.103081","url":null,"abstract":"<div><div>Precise activation of cardiac ryanodine receptor (RyR2) by small influx of Ca²⁺ during the action potential triggers the release of SR Ca²⁺ that activates contraction, a process known as Ca²⁺-induced Ca²⁺ release (CICR). Missense mutations in RyR2 often cause aberrant and unregulated Ca²⁺ releases that are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), often lethal arrhythmias. Here using CRISPR/Cas9 gene editing in human induced pluripotent stem cells (hiPSCs), we extended our previous studies to include two new arrhythmogenic mutations one, R4822H, located in S5-S6 transmembrane luminal loop near RyR2 selective filter and the other, L4865V, located on S6 segment. TIRF-imaging of voltage-clamped mutant myocytes showed that I_Ca and caffeine-triggered cytosolic Ca²⁺ rise (Fura-2 signal) or ER-GCaMP6 SR Ca²⁺ release signals were significantly suppressed in R4822H but not in L4865V myocytes. Spontaneous Ca²⁺ transients, however, persisted in both mutant lines activating both Fura-2 and ER-GCaMP6 Ca²⁺ transients in L4865V cells, but only Fura-2 Ca²⁺ transients in R4822H mutant. Spontaneous Ca²⁺ sparks igniting frequencies were similar in both mutants, but spark durations were significantly shorter. Although both of these mutations are located at S5 and S6 transmembrane regions of RyR2, their phenotypes diverge markedly. L4865V mutant does not show suppressed E-C coupling function, while R4822H mutant has completely suppressed CICR suggesting that the spontaneous beating in R4822H mutant results from remodeling of dormant Ca²⁺ signaling pathway expressed in hiPSC<img>CMs.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103081"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical but not mechanical stimulation reduce TRPA1 channel lateral mobility","authors":"Alicia Sampieri ,&nbsp;Alexander Asanov ,&nbsp;Aaron Pavel Rodríguez-Hernández ,&nbsp;Ileana Tobías-Juárez ,&nbsp;Daniel Martínez-Flores ,&nbsp;Luis Vaca","doi":"10.1016/j.ceca.2025.103059","DOIUrl":"10.1016/j.ceca.2025.103059","url":null,"abstract":"<div><div>The transient Receptor Potential Ankyrin 1 (TRPA1) is a member from the TRP superfamily of ion channels. TRPA1 channels are calcium-permeable nonselective cation channels, which are highly conserved throughout the animal kingdom. Mammals have only one member (TRPA1), while zebrafish has two (TRPA1a and TRPA1b). TRPA1 channels are activated by a plethora of stimuli, including noxious cold, mechanical stimulation, calcium, pH, reactive oxygen, and carbonyl species. In the present study we characterize the modulation of TRPA1b channel lateral mobility by Allyl isothiocyanate (AITC) and mechanical stimulation. We show that only AITC stimulation alters channel diffusion at the plasma membrane.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"131 ","pages":"Article 103059"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of K+-dependent Na+/Ca2+-exchanger subtype 4, NCKX4, by palmitoylation","authors":"By Maryam Al-Khannaq ,&nbsp;Jonathan Lytton","doi":"10.1016/j.ceca.2025.103069","DOIUrl":"10.1016/j.ceca.2025.103069","url":null,"abstract":"<div><div>Mammalian K⁺-dependent Na⁺/Ca²⁺ exchangers (NCKX), encoded by the SLC24 gene family, are crucial for maintaining Ca²⁺ homeostasis. NCKX4, widely expressed in the brain and sensory neurons, plays a key role in neuronal satiety and enamel formation. Despite its importance, the regulatory mechanisms of NCKX4 remain largely unexplored. This study investigates how palmitoylation, a post-translational modification affecting membrane proteins, regulates NCKX4 and influences its cellular localization and function.</div><div>Using Acyl-RAC and palmitate-based click-chemistry, we found that approximately 14% of NCKX4 is palmitoylated at steady-state in both endogenous and transfected systems. The level of this modification is highly dynamic, being regulated by inhibitors of palmitoylation (2-bromopalmitate) and depalmitoylation (palmostatin B), resulting in greater than a two-fold decrease or increase, respectively. Site-directed mutagenesis of six cysteine residues revealed two key sites (Cys118 and Cys425) critical for NCKX4 palmitoylation.</div><div>The subcellular distribution of palmitoylated NCKX4 was examined via proximity ligation and click-chemistry. NCKX4 was found across multiple membrane compartments, with a higher fraction localizing to the plasma membrane when palmitoylation was inhibited by 2-bromopalmitate. However, a Ca²⁺ imaging assay in HEK293T cells showed no significant change in aggregate cellular NCKX4-mediated Ca²⁺ transport upon modulation of palmitoylation status. These data suggest palmitoylation promotes internalization of the NCKX4 protein while also activating it, counter-acting effects that result in unchanged NCKX4-mediated cellular Ca²⁺ transport activity.</div><div>In summary, NCKX4 is subject to dynamic palmitoylation, which influences both distribution across cellular compartments and intrinsic Ca²⁺ transport activity. These findings contribute to our understanding of the regulation and functional roles of NCKX4 in cellular physiology.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"131 ","pages":"Article 103069"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria","authors":"Sara A. Garcia ,&nbsp;Anne M. Neumaier ,&nbsp;Michael Kohlhaas ,&nbsp;Anton Xu ,&nbsp;Alexander Nickel ,&nbsp;Katharina J. Ermer ,&nbsp;Luzia Enzner ,&nbsp;Christoph Maack ,&nbsp;Vasco Sequeira ,&nbsp;Christopher N. Johnson","doi":"10.1016/j.ceca.2025.103056","DOIUrl":"10.1016/j.ceca.2025.103056","url":null,"abstract":"<div><div>Mitochondrial calcium (Ca²⁺) uptake and factors that regulate this process have been an area of immense interest given the roles in cellular energetics. Here, we have investigated the ability of the Ca²⁺ sensing protein Calmodulin (CaM) to modify the function of the Mitochondrial Ca²⁺ Uniporter (MCU). Our data leveraged recombinantly produced CaM and mitochondria isolated from healthy and MCU impaired/diseased mice (Barth syndrome model). We found CaM enhanced Ca²⁺ uptake in both the absence and presence of CaMKII inhibition (KN93 as well as AIP). Mitochondria lacking function MCU (Barth syndrome model) validated that MCU was responsible for Ca²⁺ uptake in our experiments. Control experiments demonstrate that the observed CaM enhancement does not arise from CaM Ca²⁺ buffering. Fitting the Ca²⁺fluorescence data supported a monophasic decay process where the presence of CaM yielded enhanced kinetic rates of Ca²⁺ uptake. This CaM enhancement effect persisted in the presence of PTP impairment (cyclosporin), and subtle modification to the CaM protein sequence (D131E) revealed that an intact CaM-C domain Ca²⁺ binding was required for enhancement of MCU function.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"131 ","pages":"Article 103056"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein diversity in store-operated calcium entry components and their related variants.","authors":"Mélanie Robitaille","doi":"10.1016/j.ceca.2025.103066","DOIUrl":"10.1016/j.ceca.2025.103066","url":null,"abstract":"<p><p>Protein diversity is a fundamental biological process that enhances the functional complexity of cellular signaling pathways. This diversity arises through multiple molecular mechanisms such as gene duplication, alternative splicing, and alternative translation initiation, which together expand the proteome landscape. Calcium signaling showcases this diversity, with several channels, pumps, and regulatory proteins expressed as multiple isoforms and variants. Within the store-operated calcium entry pathway, protein diversity is evident in the existence of distinct paralogs of ORAI channels and STIM proteins. The additional presence of numerous isoforms and variants of ORAI and STIM shapes the store-operated calcium entry pathway, providing flexibility to cellular calcium regulation in various contexts. Deciphering how protein diversity modulates store-operated calcium entry function is essential for advancing our understanding of calcium signaling in both health and disease.</p>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"131 ","pages":"103066"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histamine 1 receptors and reverse-mode Na+/Ca2+ exchanger drive extracellular Na+-dependent intracellular Ca2+ oscillations in human cerebrovascular endothelial cells","authors":"Valentina Brunetti ,&nbsp;Roberto Berra-Romani ,&nbsp;Nayeli Coyotl-Santiago ,&nbsp;Yair Esquitin-Gonzalez ,&nbsp;Giorgia Chinigò ,&nbsp;Gerardo Rosario Biella ,&nbsp;Francesco Moccia ,&nbsp;Giorgia Scarpellino","doi":"10.1016/j.ceca.2025.103067","DOIUrl":"10.1016/j.ceca.2025.103067","url":null,"abstract":"<div><div>Cerebrovascular endothelial cells represent the core component of the blood-brain barrier, (BBB) which plays a critical role in regulating the local ionic microenvironment around the synapses. Therefore, cerebrovascular endothelial cells experience dramatic changes in the extracellular concentrations of potassium and sodium ions during intense neuronal firing or pathological conditions, such as spreading depression.</div><div>Herein, we assessed the mechanisms by which a reduction in extracellular sodium concentration ([Na⁺]_o) triggers complex Ca²⁺ signals in the hCMEC/D3 cell line, which is the most widespread model of human BBB.</div><div>We demonstrate that lowering the [Na⁺]_o elicits a variety of Ca²⁺ signals, including monotonic increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i) and repetitive oscillations in [Ca²⁺]_i, which are triggered by the reverse-mode Na⁺/Ca²⁺ exchanger and histamine 1 receptor (H1R). Furthermore, we provide the first evidence that H1R may play a critical role in translating a reduction in [Na⁺]_o into the activation of phospholipase C and following production of inositol triphosphate (InsP₃), thereby inducing the rhythmic activation of InsP₃ receptors on the endoplasmic reticulum (ER) and progressive depletion of the ER Ca²⁺ pool. The fall in the ER Ca²⁺ concentration leads to quick Store-Operated Ca²⁺ Entry activation, which maintains the intracellular Ca²⁺ oscillations by rapidly refilling the ER Ca²⁺ store. The endothelial Ca²⁺ oscillations induced by the reduction in [Na⁺]_o may then lead to nitric oxide release.</div><div>These findings, therefore, shed novel light on the mechanisms whereby G_q protein coupled receptors (G_qPCRs) can shape endothelial Ca²⁺ signaling and Ca²⁺-dependent events at the human neurovascular unit.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"131 ","pages":"Article 103067"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144886537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAADP-mediated calcium release promotes angiopoietin 2 secretion by regulating Rab46-dependent Weibel-Palade body trafficking","authors":"Ryan D. Murray ,&nbsp;Melissa Rose ,&nbsp;Katarina T. Miteva ,&nbsp;David J. Beech ,&nbsp;Lynn McKeown","doi":"10.1016/j.ceca.2025.103068","DOIUrl":"10.1016/j.ceca.2025.103068","url":null,"abstract":"<div><div>Angiopoietin2 (Ang2), a regulator of angiogenesis, is stored with other pro-inflammatory and pro-thrombotic mediators, in endothelial-specific vesicles called Weibel-Palade bodies (WPBs). Acute stimulation of endothelial cells with histamine, delays Ang2 secretion by activating Rab46-specific trafficking of Ang2-containing WPBs to the microtubule organising centre (MTOC), where they persist until Ca²⁺ binds to the EF-hand of Rab46, enabling detachment. Here, using Ca²⁺ imaging and high-resolution light microscopy, we pharmacologically investigated the contribution of endolysosomal two-pore channel proteins (TPC) to the Ca²⁺ signal necessary for WPB detachment and Ang2 secretion. We show an increase in the histamine-evoked clustering of Rab46 (and thus WPBs) at the MTOC in the presence of TPC inhibitors Ned-19 and tetrandrine, and a decrease in the presence of a TPC2 agonist, TPC2-A1-N. Histamine-evoked secretion of Ang2 was decreased by pharmacological inhibition of TPC channels but potentiated in the presence of TPC2-A1-N. These data suggest that histamine-mediated Ca²⁺ release via TPC2 channels is necessary for the Rab46-dependent detachment of Ang2-positive WPBs from the MTOC and thus Ang2 secretion.</div></div><div><h3>Summary</h3><div>Ca²⁺ binding to the EF-hand of Rab46 in endothelial cells has previously been reported but the molecular mechanisms and functional relevance are unclear. Here, the authors show that Ca²⁺ released from TPC channels regulates the detachment of Rab46-positive WPBs from the MTOC, which thereby promotes secretion of Ang2.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"131 ","pages":"Article 103068"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}