Cell calcium最新文献

{"title":"ELD607 specifically traffics Orai1 to the lysosome leading to inhibition of store operated calcium entry","authors":"Alexandra S. Goriounova ,&nbsp;M. Flori Sassano ,&nbsp;Joe A. Wrennall ,&nbsp;Robert Tarran","doi":"10.1016/j.ceca.2024.102945","DOIUrl":"10.1016/j.ceca.2024.102945","url":null,"abstract":"<div><p>Orai1 is a plasma membrane Ca²⁺ channel involved in store operated calcium entry (SOCE). SOCE can regulate cell growth, exocytosis, gene expression and inflammation. We previously found that short palate lung and nasal epithelial clone 1′s (SPLUNC1) sixth α-helix (α6) bound Orai1 to inhibit SOCE. SPLUNC1 was not proteolytically stable, so we developed ELD607, an 11 amino acid peptide based on SPLUNC1’s α6 region which was more stable and more potent than SPLUNC1/α6. Here, we studied ELD607’s mechanism of action. We overexpressed either Orai1-HA or Orai1-YFP in HEK293T cells to probe ELD607-Orai1 interactions by confocal microscopy. We also measured changes in Fluo-4 fluorescence in a multiplate reader as a marker of cytoplasmic Ca²⁺ levels. ELD607 internalized Orai1 independently of STIM1. Both 15 min and 3 h exposure to ELD607 similarly depleted Orai1 in the plasma membrane. However, 3 h exposure to ELD607 yielded greater inhibition of SOCE. ELD607 continued to colocalize with Orai1 after internalization and this process was dependent on the presence of the ubiquitin ligase NEDD4.2. Similarly, ELD607 increased the colocalization between Orai1 and ubiquitin. ELD607 also increased the colocalization between Orai1 and Rab5 and 7, but not Rab11, suggesting that Orai1 trafficked through early and late but not recycling endosomes. Finally, ELD607 caused Orai1, but not Orai2, Orai3, or STIM1 to traffic to lysosomes. We conclude that ELD607 rapidly binds to Orai1 and works in an identical fashion as full length SPLUNC1 by internalizing Orai1 and sending it to lysosomes, leading to a decrease in SOCE.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102945"},"PeriodicalIF":4.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0143416024001039/pdfft?md5=fb9b28cebc700529d56816f0ae473c7a&pid=1-s2.0-S0143416024001039-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142075753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duchenne muscular dystrophy skeletal muscle cells derived from human induced pluripotent stem cells recapitulate various calcium dysregulation pathways","authors":"Arnaud Delafenêtre ,&nbsp;Charles-Albert Chapotte-Baldacci ,&nbsp;Léa Dorémus ,&nbsp;Emmanuelle Massouridès ,&nbsp;Marianne Bernard ,&nbsp;Matthieu Régnacq ,&nbsp;Jérôme Piquereau ,&nbsp;Aurélien Chatelier ,&nbsp;Christian Cognard ,&nbsp;Christian Pinset ,&nbsp;Stéphane Sebille","doi":"10.1016/j.ceca.2024.102943","DOIUrl":"10.1016/j.ceca.2024.102943","url":null,"abstract":"<div><p>Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in premature death. As a major secondary event, an abnormal elevation of the intracellular calcium concentration in the dystrophin-deficient muscle contributes to disease progression in DMD. In this study, we investigated the specific functional features of induced pluripotent stem cell-derived muscle cells (hiPSC-skMCs) generated from DMD patients to regulate intracellular calcium concentration. As compared to healthy hiPSC-skMCs, DMD hiPSC-skMCs displayed specific spontaneous calcium signatures with high levels of intracellular calcium concentration. Furthermore, stimulations with electrical field or with acetylcholine perfusion induced higher calcium response in DMD hiPSC-skMCs as compared to healthy cells. Finally, Mn2+ quenching experiments demonstrated high levels of constitutive calcium entries in DMD hiPSC-skMCs as compared to healthy cells. Our findings converge on the fact that DMD hiPSC-skMCs display intracellular calcium dysregulation as demonstrated in several other models. Observed calcium disorders associated with RNAseq analysis on these DMD cells highlighted some mechanisms, such as spontaneous and activated sarcoplasmic reticulum (SR) releases or constitutive calcium entries, known to be disturbed in other dystrophin-deficient models. However, store operated calcium entries (SOCEs) were not found to be dysregulated in our DMD hiPSC-skMCs model. These results suggest that all the mechanisms of calcium impairment observed in other animal models may not be as pronounced in humans and could point to a preference for certain mechanisms that could correspond to major molecular targets for DMD therapies.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102943"},"PeriodicalIF":4.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0143416024001015/pdfft?md5=8264d1db13ed561425b5160803383264&pid=1-s2.0-S0143416024001015-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remodeling Ca2+ dynamics by targeting a promising E-box containing G-quadruplex at ORAI1 promoter in triple-negative breast cancer","authors":"Oishika Chatterjee ,&nbsp;Jagannath Jana ,&nbsp;Suman Panda ,&nbsp;Anindya Dutta ,&nbsp;Akshay Sharma ,&nbsp;Suman Saurav ,&nbsp;Rajender K. Motiani ,&nbsp;Klaus Weisz ,&nbsp;Subhrangsu Chatterjee","doi":"10.1016/j.ceca.2024.102944","DOIUrl":"10.1016/j.ceca.2024.102944","url":null,"abstract":"<div><p>ORAI1 is an intrinsic component of store-operated calcium entry (SOCE) that strictly regulates Ca²⁺ influx in most non-excitable cells. ORAI1 is overexpressed in a wide variety of cancers, and its signal transduction has been associated with chemotherapy resistance. There is extensive proteomic interaction of ORAI1 with other channels and effectors, resulting in various altered phenotypes. However, the transcription regulation of ORAI1 is not well understood. We have found a putative G-quadruplex (G4) motif, <em>ORAI1-Pu</em>, in the upstream promoter region of the gene, having regulatory functions. High-resolution 3-D NMR structure elucidation suggests that <em>ORAI1-Pu</em> is a stable parallel-stranded G4, having a long 8-nt loop imparting dynamics without affecting the structural stability. The protruded loop further houses an E-box motif that provides a docking site for transcription factors like Zeb1. The G4 structure was also endogenously observed using Chromatin Immunoprecipitation (ChIP) with anti-G4 antibody (BG4) in the MDA-MB-231 cell line overexpressing ORAI1. Ligand-mediated stabilization suggested that the stabilized G4 represses transcription in cancer cell line MDA-MB-231. Downregulation of transcription further led to decreased Ca²⁺ entry by the SOCE pathway, as observed by live-cell Fura-2 Ca²⁺ imaging.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102944"},"PeriodicalIF":4.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142075790","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":"The many facets of TMEM63/OCaR proteins as mechanosensitive channels in lysosomes, NAADP signaling and beyond","authors":"Marc Freichel ,&nbsp;Volodymyr Tsvilovskyy ,&nbsp;Koenraad Philippaert ,&nbsp;Uwe Schulte ,&nbsp;Roger Ottenheijm","doi":"10.1016/j.ceca.2024.102942","DOIUrl":"10.1016/j.ceca.2024.102942","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102942"},"PeriodicalIF":4.3,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141911873","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":"Regulating calcium flux through AMPA glutamate receptors","authors":"Ingo H. Greger","doi":"10.1016/j.ceca.2024.102934","DOIUrl":"10.1016/j.ceca.2024.102934","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102934"},"PeriodicalIF":4.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885033","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":"TRPC1: The housekeeper of the hippocampus","authors":"Julia Skerjanz ,&nbsp;Lena Bauernhofer ,&nbsp;Kerstin Lenk ,&nbsp;Anita Emmerstorfer-Augustin ,&nbsp;Gerd Leitinger ,&nbsp;Florian Reichmann ,&nbsp;Thomas Stockner ,&nbsp;Klaus Groschner ,&nbsp;Oleksandra Tiapko","doi":"10.1016/j.ceca.2024.102933","DOIUrl":"10.1016/j.ceca.2024.102933","url":null,"abstract":"<div><p>The non-selective cation channel TRPC1 is highly expressed in the brain. Recent research shows that neuronal TRPC1 forms heteromeric complexes with TRPC4 and TRPC5, with a small portion existing as homotetramers, primarily in the ER. Given that most studies have focused on the role of heteromeric TRPC1/4/5 complexes, it is crucial to investigate the specific role of homomeric TRPC1 in maintaining brain homeostasis. This review highlights recent findings on TRPC1 in the brain, with a focus on the hippocampus, and compiles the latest data on modulators and their binding sites within the TRPC1/4/5 subfamily to stimulate new research on more selective TRPC1 ligands.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102933"},"PeriodicalIF":4.3,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0143416024000915/pdfft?md5=a02753421b5354fe1513b6074ad37c26&pid=1-s2.0-S0143416024000915-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141843879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periphery Pre-S1 and S1 helix nexus for PIP2 at TRPC3 channel","authors":"Jinhyeong Kim ,&nbsp;Kyu Pil Lee ,&nbsp;Insuk So","doi":"10.1016/j.ceca.2024.102932","DOIUrl":"10.1016/j.ceca.2024.102932","url":null,"abstract":"<div><p>Transient receptor potential canonical 3 (TRPC3) is a calcium-permeable, non-selective cation channel known to be regulated by components of the phospholipase C (PLC)-mediated signaling pathway, such as Ca²⁺, diacylglycerol (DAG) and phosphatidylinositol 4,5-biphosphate (PI(4,5)P₂). However, the molecular gating mechanism by these regulators is not yet fully understood, especially its regulation by PI(4,5)P₂, despite the importance of this channel in cardiovascular pathophysiology. Recently, Clarke et al. (2024) have reported that PI(4,5)P₂ is a positive modulator for TRPC3 using molecular dynamics simulations and patch-clamp techniques. They have demonstrated a multistep gating mechanism of TRPC3 with the binding of PI(4,5)P₂ to the lipid binding site located at the pre-S1/S1 nexus, and the propagation of PI(4,5)P₂ sensing to the pore domain via a salt bridge between the TRP helix and the S4–S5 linker.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102932"},"PeriodicalIF":4.3,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141849038","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":"Interstitial cell of Cajal-like cells (ICC-LC) exhibit dynamic spontaneous activity but are not functionally innervated in mouse urethra","authors":"Neha Gupta ,&nbsp;Salah A. Baker ,&nbsp;Kenton M. Sanders ,&nbsp;Caoimhin S. Griffin ,&nbsp;Gerard P. Sergeant ,&nbsp;Mark A. Hollywood ,&nbsp;Keith D. Thornbury ,&nbsp;Bernard T. Drumm","doi":"10.1016/j.ceca.2024.102931","DOIUrl":"10.1016/j.ceca.2024.102931","url":null,"abstract":"<div><p>Urethral smooth muscle cells (USMC) contract to occlude the internal urethral sphincter during bladder filling. Interstitial cells also exist in urethral smooth muscles and are hypothesized to influence USMC behaviours and neural responses. These cells are similar to Kit⁺ interstitial cells of Cajal (ICC), which are gastrointestinal pacemakers and neuroeffectors. Isolated urethral ICC-like cells (ICC-LC) exhibit spontaneous intracellular Ca²⁺ signalling behaviours that suggest these cells may serve as pacemakers or neuromodulators similar to ICC in the gut, although observation and direct stimulation of ICC-LC within intact urethral tissues is lacking. We used mice with cell-specific expression of the Ca²⁺ indicator, GCaMP6f, driven off the endogenous promoter for <em>Kit</em> (Kit-GCaMP6f mice) to identify ICC-LC <em>in situ</em> within urethra muscles and to characterize spontaneous and nerve-evoked Ca²⁺ signalling. ICC-LC generated Ca²⁺ waves spontaneously that propagated on average 40.1 ± 0.7 μm, with varying amplitudes, durations, and spatial spread. These events originated from multiple firing sites in cells and the activity between sites was not coordinated. ICC-LC in urethra formed clusters but not interconnected networks. No evidence for entrainment of Ca²⁺ signalling between ICC-LC was obtained. Ca²⁺ events in ICC-LC were unaffected by nifedipine but were abolished by cyclopiazonic acid and decreased by an antagonist of Orai Ca²⁺ channels (GSK-7975A). Phenylephrine increased Ca²⁺ event frequency but a nitric oxide donor (DEA-NONOate) had no effect. Electrical field stimulation (EFS, 10 Hz) of intrinsic nerves, which evoked contractions of urethral rings and increased Ca²⁺ event firing in USMC, failed to evoke responses in ICC-LC. Our data suggest that urethral ICC-LC are spontaneously active but are not regulated by autonomic neurons.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102931"},"PeriodicalIF":4.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0143416024000897/pdfft?md5=b7812ffdecf9e29cc0881b72c750836c&pid=1-s2.0-S0143416024000897-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141783399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac Na-Ca exchanger “tunes-out” at high intracellular [Na]","authors":"Donald M. Bers","doi":"10.1016/j.ceca.2024.102930","DOIUrl":"10.1016/j.ceca.2024.102930","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102930"},"PeriodicalIF":4.3,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141783448","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":"Septin regulation of Orai-mediated Ca2+ entry - a novel target for neurodegeneration","authors":"Gaiti Hasan","doi":"10.1016/j.ceca.2024.102929","DOIUrl":"10.1016/j.ceca.2024.102929","url":null,"abstract":"<div><p>Aberrant Ca²⁺ signaling is an early hallmark of multiple neurodegenerative syndromes including Alzheimer's and Parkinson's disease (AD and PD) as well as classes of rare genetic disorders such as Spinocebellar Ataxias. Therapeutic strategies that target aberrant Ca²⁺ signals whilst allowing normal neuronal Ca²⁺ signals have been a challenge. In a recent study Princen et al., performed a screen in the tauP301L cell model of AD for drugs that could specifically ameliorate the excess Ca²⁺ entry observed. They identified a class of compounds referred to as ReS19-T that interact with Septins, previously identified as regulators of the Store-operated Ca²⁺ entry channel Orai. Drug treatment of the cellular model, a mouse model and human iPSC derived neurons alleviate cellular and systemic deficits associated with tauP301L. Comparison of Septin filament architecture in disease conditions with and without the drug treatment indicate that excess Ca²⁺ entry is a consequence of abnormal Septin filament architecture resulting in aberrant ER-PM contacts. The importance of membrane contacts for maintaining precise cellular signaling has been recognized previously. However, the molecular mechanism by which Septin filaments organize the ER-PM junctions to regulate Ca²⁺ entry through Orai remains to be fully understood.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102929"},"PeriodicalIF":4.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632763","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}