Pub Date : 2025-07-31DOI: 10.1016/j.ceca.2025.103059
Alicia Sampieri , Alexander Asanov , Aaron Pavel Rodríguez-Hernández , Ileana Tobías-Juárez , Daniel Martínez-Flores , Luis Vaca
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.
{"title":"Chemical but not mechanical stimulation reduce TRPA1 channel lateral mobility","authors":"Alicia Sampieri , Alexander Asanov , Aaron Pavel Rodríguez-Hernández , Ileana Tobías-Juárez , Daniel Martínez-Flores , 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":"2025-07-31","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}
Pub Date : 2025-07-19DOI: 10.1016/j.ceca.2025.103056
Sara A. Garcia , Anne M. Neumaier , Michael Kohlhaas , Anton Xu , Alexander Nickel , Katharina J. Ermer , Luzia Enzner , Christoph Maack , Vasco Sequeira , Christopher N. Johnson
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.
{"title":"Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria","authors":"Sara A. Garcia , Anne M. Neumaier , Michael Kohlhaas , Anton Xu , Alexander Nickel , Katharina J. Ermer , Luzia Enzner , Christoph Maack , Vasco Sequeira , Christopher N. Johnson","doi":"10.1016/j.ceca.2025.103056","DOIUrl":"10.1016/j.ceca.2025.103056","url":null,"abstract":"<div><div>Mitochondrial calcium (Ca<sup>2+</sup>) 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 Ca<sup>2+</sup> sensing protein Calmodulin (CaM) to modify the function of the Mitochondrial Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> uptake in our experiments. Control experiments demonstrate that the observed CaM enhancement does not arise from CaM Ca<sup>2+</sup> buffering. Fitting the Ca<sup>2+</sup>fluorescence data supported a monophasic decay process where the presence of CaM yielded enhanced kinetic rates of Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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":"2025-07-19","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}
Pub Date : 2025-07-16DOI: 10.1016/j.ceca.2025.103055
Amber D. Ide , Cody T. Morrison , Christer A. Carne , Cynthia K. Damer
Copines are a family of calcium-dependent phospholipid-binding proteins found in most eukaryotic organisms. The expression of multiple copine genes is dysregulated in various types of human cancers. Yet, a common mechanistic function for copines remains enigmatic. We are studying copines in Dictyostelium, which has six copine genes (cpnA-cpnF). Cells lacking cpnA (cpnA-) exhibit many phenotypes including defects in development, chemotaxis, adhesion, and contractile vacuole (CV) function. In this study, we identified a novel link between CpnA and calcium homeostasis. We found that cpnA- cells have more phosphatidylserine (PS) exposed in the outer leaflet of the plasma membrane due to having an increased intracellular calcium concentration. The PS exposure defect and the enlarged CV defect in cpnA- cells were rescued by chelating calcium. We further investigated the role of PatA, a CV-localized Ca²⁺-ATPase responsible for pumping calcium into the CV. Although cpnA- cells expressed normal levels of patA, immunofluorescence revealed reduced PatA localization to the CV membrane. Notably, patA knockdown (patAKD) cells phenocopied cpnA- cells, displaying enlarged CVs, elevated intracellular calcium, and increased PS exposure. Taken together, our findings suggest that CpnA promotes calcium sequestration into the CV, likely by regulating PatA localization or activity. This role in calcium homeostasis provides a mechanistic framework for understanding copine function and offers insight into how calcium dysregulation associated with copines may contribute to cancer progression.
{"title":"Copine A is essential for calcium homeostasis in Dictyostelium","authors":"Amber D. Ide , Cody T. Morrison , Christer A. Carne , Cynthia K. Damer","doi":"10.1016/j.ceca.2025.103055","DOIUrl":"10.1016/j.ceca.2025.103055","url":null,"abstract":"<div><div>Copines are a family of calcium-dependent phospholipid-binding proteins found in most eukaryotic organisms. The expression of multiple copine genes is dysregulated in various types of human cancers. Yet, a common mechanistic function for copines remains enigmatic. We are studying copines in <em>Dictyostelium</em>, which has six copine genes (<em>cpnA-cpnF</em>). Cells lacking <em>cpnA</em> (<em>cpnA-</em>) exhibit many phenotypes including defects in development, chemotaxis, adhesion, and contractile vacuole (CV) function. In this study, we identified a novel link between CpnA and calcium homeostasis. We found that <em>cpnA-</em> cells have more phosphatidylserine (PS) exposed in the outer leaflet of the plasma membrane due to having an increased intracellular calcium concentration. The PS exposure defect and the enlarged CV defect in <em>cpnA-</em> cells were rescued by chelating calcium. We further investigated the role of PatA, a CV-localized Ca²⁺-ATPase responsible for pumping calcium into the CV. Although <em>cpnA-</em> cells expressed normal levels of <em>patA</em>, immunofluorescence revealed reduced PatA localization to the CV membrane. Notably, <em>patA</em> knockdown (<em>patA<sup>KD</sup></em>) cells phenocopied <em>cpnA-</em> cells, displaying enlarged CVs, elevated intracellular calcium, and increased PS exposure. Taken together, our findings suggest that CpnA promotes calcium sequestration into the CV, likely by regulating PatA localization or activity. This role in calcium homeostasis provides a mechanistic framework for understanding copine function and offers insight into how calcium dysregulation associated with copines may contribute to cancer progression.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103055"},"PeriodicalIF":4.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687286","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}
Pub Date : 2025-07-08DOI: 10.1016/j.ceca.2025.103054
Xu Han , Jinfang Song , Zihui Geng , Runxin Li , Bingjin Li
Calcium imaging has emerged as a pivotal technique for monitoring neuronal and glial activity, gaining widespread recognition in neuroscience research. This method primarily utilizes genetically encoded calcium indicators (GECIs) or synthetic fluorescent dyes to detect physiologically relevant calcium dynamics. Despite being one of the most prevalent mental disorders, depression's pathogenesis remains poorly understood. Calcium imaging serves as a powerful tool to identify depression-related cell types and neural circuits. This review systematically summarizes the evolution of calcium indicators and their integration with behavioral paradigms, electrophysiology, optogenetics, and chemogenetics to elucidate cellular and circuit mechanisms underlying depression. In addition, calcium imaging in depression and other disease comorbidities is also discussed. These synthesized findings establish a framework for developing precision-targeted antidepressant interventions.
{"title":"Calcium imaging: Unraveling the neurobiological mechanisms of depression across cellular and circuit dimensions","authors":"Xu Han , Jinfang Song , Zihui Geng , Runxin Li , Bingjin Li","doi":"10.1016/j.ceca.2025.103054","DOIUrl":"10.1016/j.ceca.2025.103054","url":null,"abstract":"<div><div>Calcium imaging has emerged as a pivotal technique for monitoring neuronal and glial activity, gaining widespread recognition in neuroscience research. This method primarily utilizes genetically encoded calcium indicators (GECIs) or synthetic fluorescent dyes to detect physiologically relevant calcium dynamics. Despite being one of the most prevalent mental disorders, depression's pathogenesis remains poorly understood. Calcium imaging serves as a powerful tool to identify depression-related cell types and neural circuits. This review systematically summarizes the evolution of calcium indicators and their integration with behavioral paradigms, electrophysiology, optogenetics, and chemogenetics to elucidate cellular and circuit mechanisms underlying depression. In addition, calcium imaging in depression and other disease comorbidities is also discussed. These synthesized findings establish a framework for developing precision-targeted antidepressant interventions.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103054"},"PeriodicalIF":4.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596591","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}
Dietary calcium intake modifies the action of active vitamin D [1,25(OH)2D3], which promotes the expression of transient receptor potential vanilloid (TRPV) 6, an epithelial calcium channel, to initiate intestinal calcium absorption in response to biological requirements. However, it is unclear whether the change caused by dietary intake results from endocrine regulation or the direct responses to luminal contents. In this study, to reveal the underlying mechanisms of intestinal calcium transport in response to dietary intake, we assessed the early postprandial responses in mice.
Although mice lacking intestinal vitamin D receptor function (Int Vdr-) exhibited severe calcium deficiency, a high-calcium diet (1 % calcium) containing 2-fold calcium compared to a control diet reversed impaired calcium absorption and compensated for the mechanisms of 1,25(OH)2D3-dependent transcellular calcium transport. Additionally, the calcium-sensing receptor (CaSR) was abundantly present at the basolateral site in the intestine and the signals were emphasized by a high-calcium diet.
To examine the direct response of intestinal epithelium to dietary intake, wild-type (Int Vdr+) and Int Vdr- mice were fed a control or high-calcium diet for 30- or 60-min after 23 h fasting. Serum glucose levels increased 30 min post-feeding in either genotype. TRPV6 expression increased 30 min post-feeding, whereas serum calcium levels were unaltered, suggesting that dietary intake stimulates TRPV6 expression.
These data suggest that the regulation of calcium absorption activated immediately after feeding differs from the mechanism involving endocrine responses. Factors altered in the early phase of feeding, such as glucose, may contribute to the regulation of calcium absorption.
{"title":"Dietary calcium intake controls epithelial expression of TRPV6 independent of 1,25(OH)2D3 endocrine signaling","authors":"Hinata Tanishige , Atsushi Uekawa , Hitoki Yamanaka , Shigeaki Kato , Ritsuko Masuyama","doi":"10.1016/j.ceca.2025.103053","DOIUrl":"10.1016/j.ceca.2025.103053","url":null,"abstract":"<div><div>Dietary calcium intake modifies the action of active vitamin D [1,25(OH)<sub>2</sub>D<sub>3</sub>], which promotes the expression of transient receptor potential vanilloid (TRPV) 6, an epithelial calcium channel, to initiate intestinal calcium absorption in response to biological requirements. However, it is unclear whether the change caused by dietary intake results from endocrine regulation or the direct responses to luminal contents. In this study, to reveal the underlying mechanisms of intestinal calcium transport in response to dietary intake, we assessed the early postprandial responses in mice.</div><div>Although mice lacking intestinal vitamin D receptor function (<em>Int Vdr-</em>) exhibited severe calcium deficiency, a high-calcium diet (1 % calcium) containing 2-fold calcium compared to a control diet reversed impaired calcium absorption and compensated for the mechanisms of 1,25(OH)<sub>2</sub>D<sub>3</sub>-dependent transcellular calcium transport. Additionally, the calcium-sensing receptor (CaSR) was abundantly present at the basolateral site in the intestine and the signals were emphasized by a high-calcium diet.</div><div>To examine the direct response of intestinal epithelium to dietary intake, wild-type (<em>Int Vdr+</em>) and <em>Int Vdr-</em> mice were fed a control or high-calcium diet for 30- or 60-min after 23 h fasting. Serum glucose levels increased 30 min post-feeding in either genotype. TRPV6 expression increased 30 min post-feeding, whereas serum calcium levels were unaltered, suggesting that dietary intake stimulates TRPV6 expression.</div><div>These data suggest that the regulation of calcium absorption activated immediately after feeding differs from the mechanism involving endocrine responses. Factors altered in the early phase of feeding, such as glucose, may contribute to the regulation of calcium absorption.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103053"},"PeriodicalIF":4.3,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665828","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}
The pleiotropic cytokine macrophage migration inhibitory factor (MIF) elevates sarcoplasmic reticulum (SR) Ca2+ content and enhances Ca2+ transient in cardiac muscle. Our imaging and immunoblot data indicated that the MIF-evoked effect is caused mainly by the phosphorylation of the SR Ca2+-pump regulator phospholamban (PLN). Gene expression data suggested that the cluster of differentiation 74 (CD74) and the C-X-C motif chemokine receptor 7 (CXCR7) form a major MIF receptor complex in cardiomyocytes, but CXCR7 activation alone seemed sufficient to exert the MIF-evoked effect. Our pharmacological assessments suggested that phosphoinositide 3-kinase (PI3K), AKT kinase and endothelial nitric oxide synthase (eNOS) were continuously stimulated in the downstream of CXCR7 activation. Furthermore, NO thus generated likely reacted to activate Ca2+/calmodulin-dependent protein kinase II (CaMKII), leading to PLN phosphorylation and subsequent SR Ca2+-pump activation. Therefore, the CXCR7-PI3K-AKT-eNOS-CaMKII-PLN axis is proposed as a central pathway for MIF-evoked potentiation of cardiac Ca2+ signaling.
{"title":"Macrophage migration inhibitory factor induces phospholamban phosphorylation in cardiac muscle","authors":"Zihan Tang , Feng Liu , Miyuki Nishi , Fabienne Mackay , Mutsuo Harada , Hiroshi Takeshima","doi":"10.1016/j.ceca.2025.103051","DOIUrl":"10.1016/j.ceca.2025.103051","url":null,"abstract":"<div><div>The pleiotropic cytokine macrophage migration inhibitory factor (MIF) elevates sarcoplasmic reticulum (SR) Ca<sup>2+</sup> content and enhances Ca<sup>2+</sup> transient in cardiac muscle. Our imaging and immunoblot data indicated that the MIF-evoked effect is caused mainly by the phosphorylation of the SR Ca<sup>2+</sup>-pump regulator phospholamban (PLN). Gene expression data suggested that the cluster of differentiation 74 (CD74) and the C-X-C motif chemokine receptor 7 (CXCR7) form a major MIF receptor complex in cardiomyocytes, but CXCR7 activation alone seemed sufficient to exert the MIF-evoked effect. Our pharmacological assessments suggested that phosphoinositide 3-kinase (PI3K), AKT kinase and endothelial nitric oxide synthase (eNOS) were continuously stimulated in the downstream of CXCR7 activation. Furthermore, NO thus generated likely reacted to activate Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII), leading to PLN phosphorylation and subsequent SR Ca<sup>2+</sup>-pump activation. Therefore, the CXCR7-PI3K-AKT-eNOS-CaMKII-PLN axis is proposed as a central pathway for MIF-evoked potentiation of cardiac Ca<sup>2+</sup> signaling.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103051"},"PeriodicalIF":4.3,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144654931","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}
Pub Date : 2025-07-03DOI: 10.1016/j.ceca.2025.103052
Ophélie Champion , Jacek J. Litewka , Pawel E. Ferdek , Geert Bultynck
VDAC1, a large conductance channel in the outer mitochondrial membrane, plays a crucial role in mitochondrial physiology. VDAC1 supports cellular metabolism and survival by serving as a mitochondrial Ca2+-uptake and ATP-exit system. Conversely, VDAC1 also contributes to apoptosis by forming oligomeric pores mediating cytochrome c release. Recently, Oflaz et al., EMBO J, 2025, identified the Ca2+-binding protein Annexin A5 as a dynamic, Ca2+-dependent switch that enhances VDAC1’s Ca2+-transport function while at the same time preventing pro-apoptotic VDAC1 oligomer formation.
{"title":"VDAC1 as Janus in cell death and survival: Annexin A5 to the rescue","authors":"Ophélie Champion , Jacek J. Litewka , Pawel E. Ferdek , Geert Bultynck","doi":"10.1016/j.ceca.2025.103052","DOIUrl":"10.1016/j.ceca.2025.103052","url":null,"abstract":"<div><div>VDAC1, a large conductance channel in the outer mitochondrial membrane, plays a crucial role in mitochondrial physiology. VDAC1 supports cellular metabolism and survival by serving as a mitochondrial Ca<sup>2+</sup>-uptake and ATP-exit system. Conversely, VDAC1 also contributes to apoptosis by forming oligomeric pores mediating cytochrome c release. Recently, Oflaz et al., EMBO J, 2025, identified the Ca<sup>2+</sup>-binding protein Annexin A5 as a dynamic, Ca<sup>2+</sup>-dependent switch that enhances VDAC1’s Ca<sup>2+</sup>-transport function while at the same time preventing pro-apoptotic VDAC1 oligomer formation.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103052"},"PeriodicalIF":4.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572386","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}
Pub Date : 2025-07-02DOI: 10.1016/j.ceca.2025.103048
Yuan Lin , Yang Bai , Alejandro Martin-Avila , Wei Li , Xujun Wu , Edward Ziff , Wen-Biao Gan
Introduction
Presenilin (PS) gene mutations cause memory impairment in early-onset familial Alzheimer’s disease (FAD), but the underlying mechanisms remain unclear.
Methods
We examined the effects of the PS1 M146V FAD mutation on motor learning, motor learning-related changes in neuronal Ca2+activity and CREB phosphorylation in the primary motor cortex.
Results
We found that PS1 M146V knock-in mice displayed long-term deficiencies in motor skill learning. Ca2+ levels are altered in a cortical layer and neuron type-specific manner in PS1 mutant mice as compared to WT control mice. Notably, while running caused a significant increase of CREB phosphorylation in WT mice, it led to a significant decrease of CREB phosphorylation in layer 5 neurons of mutant mice.
Discussion
These findings suggest that alterations of Ca2+ activity and CREB phosphorylation in deep cortical layers are early events leading to memory impairment in the PS1 mutation-related familial form of AD.
{"title":"Abnormal calcium activity and CREB phosphorylation are associated with motor memory impairment in presenilin-1 mutant knock-in mice","authors":"Yuan Lin , Yang Bai , Alejandro Martin-Avila , Wei Li , Xujun Wu , Edward Ziff , Wen-Biao Gan","doi":"10.1016/j.ceca.2025.103048","DOIUrl":"10.1016/j.ceca.2025.103048","url":null,"abstract":"<div><h3>Introduction</h3><div>Presenilin (PS) gene mutations cause memory impairment in early-onset familial Alzheimer’s disease (FAD), but the underlying mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>We examined the effects of the PS1 M146V FAD mutation on motor learning, motor learning-related changes in neuronal Ca<sup>2+</sup>activity and CREB phosphorylation in the primary motor cortex.</div></div><div><h3>Results</h3><div>We found that PS1 M146V knock-in mice displayed long-term deficiencies in motor skill learning. Ca<sup>2+</sup> levels are altered in a cortical layer and neuron type-specific manner in PS1 mutant mice as compared to WT control mice. Notably, while running caused a significant increase of CREB phosphorylation in WT mice, it led to a significant decrease of CREB phosphorylation in layer 5 neurons of mutant mice.</div></div><div><h3>Discussion</h3><div>These findings suggest that alterations of Ca<sup>2+</sup> activity and CREB phosphorylation in deep cortical layers are early events leading to memory impairment in the PS1 mutation-related familial form of AD.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103048"},"PeriodicalIF":4.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522865","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}
Pub Date : 2025-06-19DOI: 10.1016/j.ceca.2025.103050
Marta Sobolczyk-Prawda , Agnieszka Kapsa , Malwina Lisek , Julia Tomczak , Katarzyna Sobierajska , Maciej Radek , Feng Guo , Tomasz Boczek
Emerging evidence underscores the crucial role of compartmentalized Ca²⁺ and GABA signaling in the development and progression of gliomas. Our findings reveal that low GAT3 expression and high PMCA4 levels are strongly associated with poor survival outcomes in glioma patients, suggesting their involvement in tumor progression. Using C6 glioma model, we uncovered a dynamic interaction between GAT3 and PMCA4 within lipid raft microdomains, which plays a key role in fine-tuning of localized Ca2+ dynamics in response to GABA stimulation. Knockdown of PMCA4 increased resting Ca2+concentration and enhanced Ca2+ accumulation in lipid rafts following 3-min pulse GABA stimulation, significantly impairing glioma cell migration and invasion. Interestingly, the expression of Ca2+ chelator parvalbumin in rafts abolished both baseline and GABA-stimulated Ca2+ rises, effectively restoring the migratory and invasive potential of tumor cells. We further demonstrated that GAT3 interacted with calmodulin, a pivotal regulator of PMCA4, and this interaction was decreased following 24 h GABA treatment. Long-term GABA stimulation also disrupted PMCA4/GAT3 complex, overloaded lipid rafts with Ca2+ and decreased glioma invasiveness in the presence of PMCA4. In these conditions, we observed GAT3- and Ca2+/calmodulin-dependent protein kinase II-dependent CREB phosphorylation at Ser133, which was controlled by Ca2+ events in lipid rafts and required to maintain glioma invasiveness. Our study uncovers a previously unrecognized GAT3-dependent mechanism of Ca2+compartmentalization in membrane microdomains, shedding new light on its potential role in tumor behavior. Understanding these local Ca²⁺ signaling partnerships will offer valuable insights into gliomagenesis and could lead to the development of novel therapeutic strategies for glioma treatment.
{"title":"GAT3-dependent regulation of glioma invasiveness via a lipid raft-associated PMCA4 Ca2+ transporter and a downstream CaMKII/CREB signaling – implications for compartmentalized signaling in glioma tumors","authors":"Marta Sobolczyk-Prawda , Agnieszka Kapsa , Malwina Lisek , Julia Tomczak , Katarzyna Sobierajska , Maciej Radek , Feng Guo , Tomasz Boczek","doi":"10.1016/j.ceca.2025.103050","DOIUrl":"10.1016/j.ceca.2025.103050","url":null,"abstract":"<div><div>Emerging evidence underscores the crucial role of compartmentalized Ca²⁺ and GABA signaling in the development and progression of gliomas. Our findings reveal that low GAT3 expression and high PMCA4 levels are strongly associated with poor survival outcomes in glioma patients, suggesting their involvement in tumor progression. Using C6 glioma model, we uncovered a dynamic interaction between GAT3 and PMCA4 within lipid raft microdomains, which plays a key role in fine-tuning of localized Ca<sup>2+</sup> dynamics in response to GABA stimulation. Knockdown of PMCA4 increased resting Ca<sup>2+</sup>concentration and enhanced Ca<sup>2+</sup> accumulation in lipid rafts following 3-min pulse GABA stimulation, significantly impairing glioma cell migration and invasion. Interestingly, the expression of Ca<sup>2+</sup> chelator parvalbumin in rafts abolished both baseline and GABA-stimulated Ca<sup>2+</sup> rises, effectively restoring the migratory and invasive potential of tumor cells. We further demonstrated that GAT3 interacted with calmodulin, a pivotal regulator of PMCA4, and this interaction was decreased following 24 h GABA treatment. Long-term GABA stimulation also disrupted PMCA4/GAT3 complex, overloaded lipid rafts with Ca<sup>2+</sup> and decreased glioma invasiveness in the presence of PMCA4. In these conditions, we observed GAT3- and Ca<sup>2+</sup>/calmodulin-dependent protein kinase II-dependent CREB phosphorylation at Ser133, which was controlled by Ca<sup>2+</sup> events in lipid rafts and required to maintain glioma invasiveness. Our study uncovers a previously unrecognized GAT3-dependent mechanism of Ca<sup>2+</sup>compartmentalization in membrane microdomains, shedding new light on its potential role in tumor behavior. Understanding these local Ca²⁺ signaling partnerships will offer valuable insights into gliomagenesis and could lead to the development of novel therapeutic strategies for glioma treatment.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103050"},"PeriodicalIF":4.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490793","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}
Pub Date : 2025-06-17DOI: 10.1016/j.ceca.2025.103049
Federica De Lazzari , Simone Wanderoy , Alexander J Whitworth
The pathogenic mechanisms of LRRK2 are hotly debated but regulation of lysosomal homeostasis has emerged as a leading focus area. In recent work, Gregori et al. show that Ca2+ release through the lysosomal Two-Pore Channel 2 (TPC2) could be a significant contributor to dopaminergic neuron vulnerability.
{"title":"Calcium at the crossroads: TPC2’s role in LRRK2-linked Parkinson’s disease","authors":"Federica De Lazzari , Simone Wanderoy , Alexander J Whitworth","doi":"10.1016/j.ceca.2025.103049","DOIUrl":"10.1016/j.ceca.2025.103049","url":null,"abstract":"<div><div>The pathogenic mechanisms of LRRK2 are hotly debated but regulation of lysosomal homeostasis has emerged as a leading focus area. In recent work, Gregori et al. show that Ca<sup>2+</sup> release through the lysosomal Two-Pore Channel 2 (TPC2) could be a significant contributor to dopaminergic neuron vulnerability.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"130 ","pages":"Article 103049"},"PeriodicalIF":4.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144481519","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}
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