Pub Date : 2025-12-23DOI: 10.1016/j.ceca.2025.103107
Simran Soni, Ginpreet Kaur
Calcium serves as an important cellular messenger in neurons, which needs to be regulated at optimal concentrations intracellularly for normal functioning of nerve cells. The dysregulation of calcium represents a relatively newer target associated with several neurodegenerative disorders such as Alzheimer’s disease. The growing incidence of Alzheimer’s disease, which offers symptomatic treatments for its underlying pathology, has prompted the exploration of novel targets. It has been demonstrated that the PI3K/Akt/GSK-3β pathway is essential for neuroprotection, increasing cell survival by promoting cell division and preventing apoptosis, which are regulated by extracellular calcium. Inhibition of neuroprotective PI3K activation by calcium dyshomeostasis can lead to dephosphorylating Akt. These cause hyperphosphorylation of tau protein through the overactivation of GSK-3β, which leads to the formation of neurofibrillary tangles and deposition of amyloid protein that will exacerbate cognitive decline and Alzheimer’s disease. This comprehensive review will provide the insights of pathogenic mechanisms involved in calcium dysfunction associated with PI3K/Akt/GSK-3β signaling in the progression of the disease to identify novel targets. Also, it emphasizes emerging therapeutics, including modulators, which can be targeted to maintain the calcium level in the brain and ameliorate the pathology of the disease.
{"title":"Emerging therapeutics targeting the PI3K/Akt/GSK-3β in calcium dysregulation in Alzheimer’s disease","authors":"Simran Soni, Ginpreet Kaur","doi":"10.1016/j.ceca.2025.103107","DOIUrl":"10.1016/j.ceca.2025.103107","url":null,"abstract":"<div><div>Calcium serves as an important cellular messenger in neurons, which needs to be regulated at optimal concentrations intracellularly for normal functioning of nerve cells. The dysregulation of calcium represents a relatively newer target associated with several neurodegenerative disorders such as Alzheimer’s disease. The growing incidence of Alzheimer’s disease, which offers symptomatic treatments for its underlying pathology, has prompted the exploration of novel targets. It has been demonstrated that the PI3K/Akt/GSK-3β pathway is essential for neuroprotection, increasing cell survival by promoting cell division and preventing apoptosis, which are regulated by extracellular calcium. Inhibition of neuroprotective PI3K activation by calcium dyshomeostasis can lead to dephosphorylating Akt. These cause hyperphosphorylation of tau protein through the overactivation of GSK-3β, which leads to the formation of neurofibrillary tangles and deposition of amyloid protein that will exacerbate cognitive decline and Alzheimer’s disease. This comprehensive review will provide the insights of pathogenic mechanisms involved in calcium dysfunction associated with PI3K/Akt/GSK-3β signaling in the progression of the disease to identify novel targets. Also, it emphasizes emerging therapeutics, including modulators, which can be targeted to maintain the calcium level in the brain and ameliorate the pathology of the disease.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103107"},"PeriodicalIF":4.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836666","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 : 2025-12-17DOI: 10.1016/j.ceca.2025.103106
Arpita Deb , Valeria Gomez , Yujia Cheng , Zhuoxin Li , Jinying Yang , Imtiaz Dowllah , Ngoc Nguyen , Oluwabori Adekanye , Ashley J. Smuder , Zhiyong Cheng , Bin Liu
Calcium (Ca2+) enters the mitochondria primarily through the mitochondria calcium uniporter (MCU). Conflicting results have been reported regarding the role of MCU in metabolic heart disease. Therefore, we employed a cardiomyocyte-specific MCU knockout (KO) model to assess its impact on the development of diabetic cardiomyopathy (DCM). Type 1 diabetes was induced in mice through streptozotocin (STZ) injection. The study included four groups: a wild-type (WT) control, two STZ-injected groups, designated as WT-STZ and MCUKO-STZ, and a MCUKO control. WT-STZ mice developed DCM, exhibiting contractile dysfunction (assessed by echocardiography) and ventricular arrhythmias (identified via electrocardiogram). Fluorescent imaging of isolated WT-STZ myocytes revealed impaired Ca2+ homeostasis and increased reactive oxygen species (ROS) production. Histological staining of WT-STZ cardiac tissue showed cellular hypertrophy and increased apoptosis. Mitochondrial energetics was also compromised in the WT-STZ model. MCU ablation significantly improved cardiac function in MCUKO-STZ mice, which maintained normal contractile function. Both cellular and in vivo arrhythmias were ameliorated in MCUKO-STZ. MCUKO-STZ myocytes exhibited improved Ca2+ handling and lower ROS emission. Hypertrophy and apoptosis were also alleviated in this group. Additionally, mitochondrial energetics, while not reversed, exhibited a slight trend toward improvement. Our study suggests that MCU ablation attenuates DCM progression. Inhibiting MCU-dependent Ca2+ entry may serve as a potential therapeutic strategy for type 1 diabetic cardiomyopathy by preventing arrhythmogenesis and pathological remodeling.
{"title":"Ablation of mitochondrial calcium uniporter alleviates cardiac dysfunction in type 1 diabetes","authors":"Arpita Deb , Valeria Gomez , Yujia Cheng , Zhuoxin Li , Jinying Yang , Imtiaz Dowllah , Ngoc Nguyen , Oluwabori Adekanye , Ashley J. Smuder , Zhiyong Cheng , Bin Liu","doi":"10.1016/j.ceca.2025.103106","DOIUrl":"10.1016/j.ceca.2025.103106","url":null,"abstract":"<div><div>Calcium (Ca<sup>2+</sup>) enters the mitochondria primarily through the mitochondria calcium uniporter (MCU). Conflicting results have been reported regarding the role of MCU in metabolic heart disease. Therefore, we employed a cardiomyocyte-specific MCU knockout (KO) model to assess its impact on the development of diabetic cardiomyopathy (DCM). Type 1 diabetes was induced in mice through streptozotocin (STZ) injection. The study included four groups: a wild-type (WT) control, two STZ-injected groups, designated as WT-STZ and MCU<sup>KO</sup>-STZ, and a MCU<sup>KO</sup> control. WT-STZ mice developed DCM, exhibiting contractile dysfunction (assessed by echocardiography) and ventricular arrhythmias (identified via electrocardiogram). Fluorescent imaging of isolated WT-STZ myocytes revealed impaired Ca<sup>2+</sup> homeostasis and increased reactive oxygen species (ROS) production. Histological staining of WT-STZ cardiac tissue showed cellular hypertrophy and increased apoptosis. Mitochondrial energetics was also compromised in the WT-STZ model. MCU ablation significantly improved cardiac function in MCU<sup>KO</sup>-STZ mice, which maintained normal contractile function. Both cellular and in vivo arrhythmias were ameliorated in MCU<sup>KO</sup>-STZ. MCU<sup>KO</sup>-STZ myocytes exhibited <em>improved</em> Ca<sup>2+</sup> handling and lower ROS emission. Hypertrophy and apoptosis were also alleviated in this group. Additionally, mitochondrial energetics, while not reversed, exhibited a slight trend toward improvement. Our study suggests that MCU ablation attenuates DCM progression. Inhibiting MCU-dependent Ca<sup>2+</sup> entry may serve as a potential therapeutic strategy for type 1 diabetic cardiomyopathy by preventing arrhythmogenesis and pathological remodeling.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103106"},"PeriodicalIF":4.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827055","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 : 2025-12-13DOI: 10.1016/j.ceca.2025.103105
Juan Alcalde , Ester Martín-Villar , Martin W. Berchtold , Antonio Villalobo
Extracellular vesicles (EVs), including exosomes and microvesicles, secreted by a wide range of eukaryotic cells, are now well-established mediators of intercellular communication, acting through their uptake by recipient cells at local or distant sites. This occurs after delivering their cargo, a variety of RNAs, lipids, and proteins, which regulate many cellular functions in health and disease states. Among the exosomal cargos, the Ca2+-sensor protein calmodulin (CaM), as well as several Ca2+/CaM-regulated proteins, are frequently found in EVs, potentially playing important roles in the function of target cells. In addition, RNAs, which control the expression (mRNAs) or downregulation (miRNAs, lncRNAs) of Ca2+/CaM-regulated systems, are present in EVs, contributing to Ca2+ signaling processes when transferred into target cells. We discuss the involvement of exosomal CaM signaling systems in the pathophysiology of some high-incidence diseases affecting the heart and the nervous system. In this group, the contribution of Ca²⁺/CaM-regulated systems to tumor cells behavior in a wide range of organs is explored in more detail. In addition, some diseases of the kidneys, lungs, liver, the immune system, the eyes and the pancreas are considered. Finally, we highlight selected examples in which isolated exosomes modulating Ca²⁺/CaM pathways have been investigated as potential therapeutic agents.
{"title":"Ca2+/calmodulin-driven functions mediated by extracellular vesicles: a physiopathological perspective","authors":"Juan Alcalde , Ester Martín-Villar , Martin W. Berchtold , Antonio Villalobo","doi":"10.1016/j.ceca.2025.103105","DOIUrl":"10.1016/j.ceca.2025.103105","url":null,"abstract":"<div><div>Extracellular vesicles (EVs), including exosomes and microvesicles, secreted by a wide range of eukaryotic cells, are now well-established mediators of intercellular communication, acting through their uptake by recipient cells at local or distant sites. This occurs after delivering their cargo, a variety of RNAs, lipids, and proteins, which regulate many cellular functions in health and disease states. Among the exosomal cargos, the Ca<sup>2+</sup>-sensor protein calmodulin (CaM), as well as several Ca<sup>2+</sup>/CaM-regulated proteins, are frequently found in EVs, potentially playing important roles in the function of target cells. In addition, RNAs, which control the expression (mRNAs) or downregulation (miRNAs, lncRNAs) of Ca<sup>2+</sup>/CaM-regulated systems, are present in EVs, contributing to Ca<sup>2+</sup> signaling processes when transferred into target cells. We discuss the involvement of exosomal CaM signaling systems in the pathophysiology of some high-incidence diseases affecting the heart and the nervous system. In this group, the contribution of Ca²⁺/CaM-regulated systems to tumor cells behavior in a wide range of organs is explored in more detail. In addition, some diseases of the kidneys, lungs, liver, the immune system, the eyes and the pancreas are considered. Finally, we highlight selected examples in which isolated exosomes modulating Ca²⁺/CaM pathways have been investigated as potential therapeutic agents.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103105"},"PeriodicalIF":4.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780275","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 : 2025-12-10DOI: 10.1016/j.ceca.2025.103093
Luis Fernando Delgadillo-Silva , Karen Dakessian , Audrey Provencher-Girard , William E. Louch , Guy A. Rutter
Defective insulin secretion is a hallmark of diabetes mellitus. Glucose-induced Ca2+ oscillations are critical for the stimulation of insulin secretion, though the mechanisms through which these propagate across the islet are poorly understood. Here, we use beta cell-targeted GCaMP6f to explore the role of endoplasmic reticulum (ER) Ca2+ mobilization in response to submaximal (11 mM) or hyperglycemic (25 mM) glucose, mimicking diabetes. Inhibition of inositol 1,4,5-trisphosphate (IP3) receptors, and other ion channels, with 2-aminoethoxydiphenyl borate (2-APB), had minimal effects on the initial peak or intercellular connectivity provoked by 11 mM glucose. However, 2-APB lowered subsequent glucose-induced cytosolic Ca2+increases and connectivity at both 11 and 25 mM glucose. Unexpectedly, the activation of IP3 receptors with the muscarinic acetylcholine receptor agonist carbachol had minimal impact on the initial peak elicited by 11 mM glucose, but Ca2+ waves at 11 and 25 mM glucose were more poorly coordinated. To determine whether ER calcium mobilization was sufficient to initiate Ca2+ waves we next blocked sarco(endo)plasmic Ca2+ ATPase (SERCA) pumps with thapsigargin, whilst preventing plasma membrane depolarization with the KATP-channel opener, diazoxide. Under these conditions, an initial cytosolic Ca2+increase was followed by secondary Ca2+ waves that subsided slowly. The application of carbachol alongside diazoxide still enhanced Ca2+dynamics, though activity was uncoordinated. After genetic deletion of SERCA2 in beta cells, Ca2+wave frequency, but not connectivity, were lowered. Our results show that ER Ca2+ mobilization plays a relatively minor role in the initiation and propagation of Ca2+ waves in response to glucose but is needed for sustained Ca2+waves.
{"title":"ER calcium stores contribute to glucose-induced Ca2+ waves and intercellular connectivity in mouse pancreatic islets","authors":"Luis Fernando Delgadillo-Silva , Karen Dakessian , Audrey Provencher-Girard , William E. Louch , Guy A. Rutter","doi":"10.1016/j.ceca.2025.103093","DOIUrl":"10.1016/j.ceca.2025.103093","url":null,"abstract":"<div><div>Defective insulin secretion is a hallmark of diabetes mellitus. Glucose-induced Ca<sup>2+</sup> oscillations are critical for the stimulation of insulin secretion, though the mechanisms through which these propagate across the islet are poorly understood. Here, we use beta cell-targeted GCaMP6f to explore the role of endoplasmic reticulum (ER) Ca<sup>2+</sup> mobilization in response to submaximal (11 mM) or hyperglycemic (25 mM) glucose, mimicking diabetes. Inhibition of inositol 1,4,5-trisphosphate (IP<sub>3</sub>) receptors, and other ion channels, with 2-aminoethoxydiphenyl borate (2-APB), had minimal effects on the initial peak or intercellular connectivity provoked by 11 mM glucose. However, 2-APB lowered subsequent glucose-induced cytosolic Ca<sup>2+</sup>increases and connectivity at both 11 and 25 mM glucose. Unexpectedly, the activation of IP<sub>3</sub> receptors with the muscarinic acetylcholine receptor agonist carbachol had minimal impact on the initial peak elicited by 11 mM glucose, but Ca<sup>2+</sup> waves at 11 and 25 mM glucose were more poorly coordinated. To determine whether ER calcium mobilization was sufficient to initiate Ca<sup>2+</sup> waves we next blocked sarco(endo)plasmic Ca<sup>2+</sup> ATPase (SERCA) pumps with thapsigargin, whilst preventing plasma membrane depolarization with the K<sub>ATP</sub>-channel opener, diazoxide. Under these conditions, an initial cytosolic Ca<sup>2+</sup>increase was followed by secondary Ca<sup>2+</sup> waves that subsided slowly. The application of carbachol alongside diazoxide still enhanced Ca<sup>2+</sup>dynamics, though activity was uncoordinated. After genetic deletion of SERCA2 in beta cells, Ca<sup>2+</sup>wave frequency, but not connectivity, were lowered. Our results show that ER Ca<sup>2+</sup> mobilization plays a relatively minor role in the initiation and propagation of Ca<sup>2+</sup> waves in response to glucose but is needed for sustained Ca<sup>2+</sup>waves.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103093"},"PeriodicalIF":4.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145787209","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 : 2025-12-08DOI: 10.1016/j.ceca.2025.103104
Nicole M. Procacci , Gale L. Craviso , Normand Leblanc , Josette Zaklit , Jihwan Yoon , Salah A Baker , Thomas W. Gould
Chromaffin cells of the adrenal medulla exhibit spontaneous action potentials and intracellular Ca2+ responses that result in catecholamine secretion when dissociated in vitro. However, spontaneous activity in these cells is nearly abolished when splanchnic nerve input is blocked in vivo. To address this discrepancy, we examined spontaneous Ca2+ responses in chromaffin cells in an intermediate preparation, adrenal slices from transgenic mice expressing the genetically-encoded Ca2+ indicator GCaMP6f selectively in these cells. Within this preparation, the three-dimensional structure and extracellular environment surrounding chromaffin cells is retained, as is input from distal splanchnic nerve terminals, which spontaneously release the neurotransmitter acetylcholine. Chromaffin cells within these slices displayed spontaneous Ca2+ responses with frequencies and amplitudes that varied greatly within and between individual cells. However, population averages remained stable, providing a tool to measure the cellular and molecular mechanisms underlying these responses. While overall average frequencies and amplitudes of spontaneous Ca2+ responses depended on the influx of extracellular Ca2+ through voltage-gated Ca2+ channels, they did not require Ca2+ release from intracellular stores, splanchnic nerve input or activation of voltage-gated sodium channels. Together, these results suggest that spontaneous activity in chromaffin cells in adrenal slices is generated autonomously, similar to that in dissociated chromaffin cells. By contrast, spontaneous activity in chromaffin cells in intact animals likely represents a distinct form that depends on basal input from intact splanchnic nerve. This study provides a foundation to further explore the diverse mechanisms mediating chromaffin cell activation.
{"title":"GCaMP6f-expressing chromaffin cells in murine adrenal slices exhibit dynamic spontaneous calcium responses that do not require nerve input","authors":"Nicole M. Procacci , Gale L. Craviso , Normand Leblanc , Josette Zaklit , Jihwan Yoon , Salah A Baker , Thomas W. Gould","doi":"10.1016/j.ceca.2025.103104","DOIUrl":"10.1016/j.ceca.2025.103104","url":null,"abstract":"<div><div>Chromaffin cells of the adrenal medulla exhibit spontaneous action potentials and intracellular Ca<sup>2+</sup> responses that result in catecholamine secretion when dissociated in vitro. However, spontaneous activity in these cells is nearly abolished when splanchnic nerve input is blocked in vivo. To address this discrepancy, we examined spontaneous Ca<sup>2+</sup> responses in chromaffin cells in an intermediate preparation, adrenal slices from transgenic mice expressing the genetically-encoded Ca<sup>2+</sup> indicator GCaMP6f selectively in these cells. Within this preparation, the three-dimensional structure and extracellular environment surrounding chromaffin cells is retained, as is input from distal splanchnic nerve terminals, which spontaneously release the neurotransmitter acetylcholine. Chromaffin cells within these slices displayed spontaneous Ca<sup>2+</sup> responses with frequencies and amplitudes that varied greatly within and between individual cells. However, population averages remained stable, providing a tool to measure the cellular and molecular mechanisms underlying these responses. While overall average frequencies and amplitudes of spontaneous Ca<sup>2+</sup> responses depended on the influx of extracellular Ca<sup>2+</sup> through voltage-gated Ca<sup>2+</sup> channels, they did not require Ca<sup>2+</sup> release from intracellular stores, splanchnic nerve input or activation of voltage-gated sodium channels. Together, these results suggest that spontaneous activity in chromaffin cells in adrenal slices is generated autonomously, similar to that in dissociated chromaffin cells. By contrast, spontaneous activity in chromaffin cells in intact animals likely represents a distinct form that depends on basal input from intact splanchnic nerve. This study provides a foundation to further explore the diverse mechanisms mediating chromaffin cell activation.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103104"},"PeriodicalIF":4.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733566","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 : 2025-12-04DOI: 10.1016/j.ceca.2025.103101
Anja Riedel , Rebekka Medert , Sara Monaco , Enio Gjerga , Xenia Tolksdorf , Christin Richter , Michelle Malz , Meike Schrader , Vladimir Kuryshev , Martin Busch , Andreas Jungmann , Zoe Löwenthal , Koenraad Philippaert , Angela Wirth , Roger Ottenheijm , Vladimir Benes , Patrick Most , Christoph Dieterich , Mirko Völkers , Hilmar Bading , Marc Freichel
Cardiac remodeling, including hypertrophy, is associated with alterations in cytosolic Ca2+ homeostasis of cardiac myocytes that spill over into the nucleoplasm. To test whether nuclear Ca2+ signaling acts causally on the development of cardiac hypertrophy, we expressed parvalbumin to buffer nuclear Ca2+ and we blocked nuclear Ca2+-calmodulin signaling by Adeno-associated virus (AAV)-mediated expression of the calmodulin (CaM) binding-peptide nlsCaMBP4, respectively, in the nuclei of ES cell-derived (Cor.At) and neonatal rat ventricular cardiac myocytes (NRVCM). Expression of nlsCaMBP4, but not parvalbumin, leads to a significant reduction of hypertrophic growth induced by phenylephrine (PE). Expression of nlsCaMBP4 did not alter the amplitude of electrically-evoked intracellular Ca2+ transients in NRVCMs in the absence or presence of PE, and did not affect the PE-evoked increase in store-operated Ca2+ entry. Transcriptome analysis on NRVCMs expressing nlsCaMBP4 revealed that induction of classical hypertrophy markers such as ANF and BNP or MEF2 target genes (such as Srpk3, Xirp1 and Xirp2) were not reduced by nlsCaMBP4 expression. Further analysis of the nuclear Ca2+-calmodulin-regulated gene pool revealed differential expression of genes involved in mRNA translation, including the translation initiation factor subunits Eif2s1, Eif3d and Eif5, whose upregulation was absent in nlsCaMBP4-treated myocytes. Puromycin assays showed that inhibition of Ca2+-calmodulin signaling prevented catecholamine-evoked protein translation, suggesting that Ca2+-calmodulin signaling in the nucleus of cardiac myocytes regulates translation via transcriptional control mechanisms. However, future studies are needed to identify the exact molecular components and machinery that integrate Ca2+-calmodulin-dependent regulation of transcription, protein translation, and development of cardiac myocyte hypertrophy.
{"title":"Nuclear Ca2+-Calmodulin signaling in cardiac myocytes reduces catecholamine-evoked protein translation and prevents hypertrophy","authors":"Anja Riedel , Rebekka Medert , Sara Monaco , Enio Gjerga , Xenia Tolksdorf , Christin Richter , Michelle Malz , Meike Schrader , Vladimir Kuryshev , Martin Busch , Andreas Jungmann , Zoe Löwenthal , Koenraad Philippaert , Angela Wirth , Roger Ottenheijm , Vladimir Benes , Patrick Most , Christoph Dieterich , Mirko Völkers , Hilmar Bading , Marc Freichel","doi":"10.1016/j.ceca.2025.103101","DOIUrl":"10.1016/j.ceca.2025.103101","url":null,"abstract":"<div><div>Cardiac remodeling, including hypertrophy, is associated with alterations in cytosolic Ca<sup>2+</sup> homeostasis of cardiac myocytes that spill over into the nucleoplasm. To test whether nuclear Ca<sup>2+</sup> signaling acts causally on the development of cardiac hypertrophy, we expressed parvalbumin to buffer nuclear Ca<sup>2+</sup> and we blocked nuclear Ca<sup>2+</sup>-calmodulin signaling by Adeno-associated virus (AAV)-mediated expression of the calmodulin (CaM) binding-peptide nlsCaMBP4, respectively, in the nuclei of ES cell-derived (Cor.At) and neonatal rat ventricular cardiac myocytes (NRVCM). Expression of nlsCaMBP4, but not parvalbumin, leads to a significant reduction of hypertrophic growth induced by phenylephrine (PE). Expression of nlsCaMBP4 did not alter the amplitude of electrically-evoked intracellular Ca<sup>2+</sup> transients in NRVCMs in the absence or presence of PE, and did not affect the PE-evoked increase in store-operated Ca<sup>2+</sup> entry. Transcriptome analysis on NRVCMs expressing nlsCaMBP4 revealed that induction of classical hypertrophy markers such as ANF and BNP or MEF2 target genes (such as Srpk3, Xirp1 and Xirp2) were not reduced by nlsCaMBP4 expression. Further analysis of the nuclear Ca<sup>2+</sup>-calmodulin-regulated gene pool revealed differential expression of genes involved in mRNA translation, including the translation initiation factor subunits Eif2s1, Eif3d and Eif5, whose upregulation was absent in nlsCaMBP4-treated myocytes. Puromycin assays showed that inhibition of Ca<sup>2+</sup>-calmodulin signaling prevented catecholamine-evoked protein translation, suggesting that Ca<sup>2+</sup>-calmodulin signaling in the nucleus of cardiac myocytes regulates translation via transcriptional control mechanisms. However, future studies are needed to identify the exact molecular components and machinery that integrate Ca<sup>2+</sup>-calmodulin-dependent regulation of transcription, protein translation, and development of cardiac myocyte hypertrophy.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103101"},"PeriodicalIF":4.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733565","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 : 2025-11-30DOI: 10.1016/j.ceca.2025.103100
Alicia Sampieri , Alexander Asanov , Aaron Pavel Rodríguez-Hernández , Ileana Tobías-Juárez , Luis Vaca
The two main components of store-operated calcium entry (SOCE) are the ion channel Orai1 and the multifunctional protein STIM1. Recently STIM1 has been recognized as a microtubule plus end tracking protein involved in remodeling of the endoplasmic reticulum. However, the relationship between ER remodeling and SOCE are poorly understood. In the present study we have found that activation of Orai1 channels by the expression of the SOAR (STIM1 Orai activating region) from STIM1 induces Orai1 puncta formation and SOCE but does not alter the role of STIM1 in ER remodeling. Furthermore, expression of the STIM1-EB1-D (the STIM1-EB1 association domain) from STIM1 significantly reduces SOCE and prevents the traveling of STIM1 in ER projections. However, ER projections driven by EB1 remained unaffected. These findings suggest that there may be several mechanisms responsible for ER remodeling but only one in which STIM1 participates. This type of ER remodeling mechanism where STIM1 plays an active role participates in the control of SOCE.
储运钙通道（SOCE）的两个主要组成部分是离子通道Orai1和多功能蛋白STIM1。最近，STIM1被认为是参与内质网重塑的微管+末端跟踪蛋白。然而，内质网重塑与SOCE之间的关系尚不清楚。在本研究中，我们发现通过表达来自STIM1的SOAR （STIM1 Orai激活区）激活Orai1通道可诱导Orai1小点形成和SOCE，但不会改变STIM1在内质网重塑中的作用。此外，STIM1的STIM1- eb1 - d （STIM1- eb1关联结构域）的表达显著降低了SOCE，并阻止了STIM1在ER投射中的移动。然而，由EB1驱动的ER预测并未受到影响。这些发现表明，可能有几种机制负责内质网重塑，但只有STIM1参与其中。这种STIM1发挥积极作用的内质网重塑机制参与了SOCE的控制。
{"title":"The handshake between the continuous remodeling of the endoplasmic reticulum and the store-operated calcium entry","authors":"Alicia Sampieri , Alexander Asanov , Aaron Pavel Rodríguez-Hernández , Ileana Tobías-Juárez , Luis Vaca","doi":"10.1016/j.ceca.2025.103100","DOIUrl":"10.1016/j.ceca.2025.103100","url":null,"abstract":"<div><div>The two main components of store-operated calcium entry (SOCE) are the ion channel Orai1 and the multifunctional protein STIM1. Recently STIM1 has been recognized as a microtubule plus end tracking protein involved in remodeling of the endoplasmic reticulum. However, the relationship between ER remodeling and SOCE are poorly understood. In the present study we have found that activation of Orai1 channels by the expression of the SOAR (STIM1 Orai activating region) from STIM1 induces Orai1 puncta formation and SOCE but does not alter the role of STIM1 in ER remodeling. Furthermore, expression of the STIM1-EB1-D (the STIM1-EB1 association domain) from STIM1 significantly reduces SOCE and prevents the traveling of STIM1 in ER projections. However, ER projections driven by EB1 remained unaffected. These findings suggest that there may be several mechanisms responsible for ER remodeling but only one in which STIM1 participates. This type of ER remodeling mechanism where STIM1 plays an active role participates in the control of SOCE.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103100"},"PeriodicalIF":4.0,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667198","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 : 2025-11-21DOI: 10.1016/j.ceca.2025.103091
Lea Kaschek , Joanne Vialle , Gebhard Stopper , Markus D.A. Hoffmann , Sylvia Zöphel , Johanna Jansky , Nadja Küchler , Gertrud Schäfer , Alina Moter , Philipp Wendel , Frank Neumann , Claudia Schormann , Evelyn Ullrich , Leticia Prates Roma , Carsten Kummerow , Lorenz Thurner , Eva C. Schwarz , Markus Hoth
There are compelling reasons to opt for primary human natural killer (NK) cells when validating Ca2+ indicators. 1.) NK cells exhibit a high degree of vulnerability to stressors such as indicator loading or light exposure. 2.) The lack of research on NK Ca2+ signaling underscores the necessity for developing reliable assays. 3.) The increased utilization of NK cell therapies necessitates a more profound comprehension of Ca2+ dependent signal transduction. Consequently, an assay was developed to monitor cytosolic Ca2+ signals in individual NK cells simultaneously with their cytotoxic function against cancer cells. We used this assay to assess the suitability of fura-2, fura-PE3, fura-8, fura-10 or fura-red for quantifying Ca2+ signals in NK cells without compromising their cytotoxic function. In contrast to the widely used fura-2, its red-shifted derivative fura-10 did not interfere with NK cytotoxicity over several hours. It exhibited a superior signal-to-noise ratio and good dynamic range, accompanied by minimal bleaching or leakage. Fura-8 and fura-red also preserved NK cell cytotoxicity, but had other disadvantages compared to fura-10. We successfully used fura-10 to report Ca2+ signals in NK cells from blood donors and patients diagnosed with lymphoma and leukemia over several hours at 37 °C during apoptotic or necrotic killing of different cancer cells (K562, THP1, OCI-AML2, and TMD8). Additionally, we show that fura-10 is well suited to report Ca2+ signals in intact murine pancreatic islets, another stress-sensitive cell preparation. Consequently, fura-10 is an optimal choice for measuring Ca²⁺ in primary human NK cells and other primary cell preparations.
{"title":"Fura-10, unlike fura-2, is suitable for long-term calcium imaging in natural killer (NK) cells without compromising cytotoxicity and can be combined with target cell death analysis","authors":"Lea Kaschek , Joanne Vialle , Gebhard Stopper , Markus D.A. Hoffmann , Sylvia Zöphel , Johanna Jansky , Nadja Küchler , Gertrud Schäfer , Alina Moter , Philipp Wendel , Frank Neumann , Claudia Schormann , Evelyn Ullrich , Leticia Prates Roma , Carsten Kummerow , Lorenz Thurner , Eva C. Schwarz , Markus Hoth","doi":"10.1016/j.ceca.2025.103091","DOIUrl":"10.1016/j.ceca.2025.103091","url":null,"abstract":"<div><div>There are compelling reasons to opt for primary human natural killer (NK) cells when validating Ca<sup>2+</sup> indicators. 1.) NK cells exhibit a high degree of vulnerability to stressors such as indicator loading or light exposure. 2.) The lack of research on NK Ca<sup>2+</sup> signaling underscores the necessity for developing reliable assays. 3.) The increased utilization of NK cell therapies necessitates a more profound comprehension of Ca<sup>2+</sup> dependent signal transduction. Consequently, an assay was developed to monitor cytosolic Ca<sup>2+</sup> signals in individual NK cells simultaneously with their cytotoxic function against cancer cells. We used this assay to assess the suitability of fura-2, fura-PE3, fura-8, fura-10 or fura-red for quantifying Ca<sup>2+</sup> signals in NK cells without compromising their cytotoxic function. In contrast to the widely used fura-2, its red-shifted derivative fura-10 did not interfere with NK cytotoxicity over several hours. It exhibited a superior signal-to-noise ratio and good dynamic range, accompanied by minimal bleaching or leakage. Fura-8 and fura-red also preserved NK cell cytotoxicity, but had other disadvantages compared to fura-10. We successfully used fura-10 to report Ca<sup>2+</sup> signals in NK cells from blood donors and patients diagnosed with lymphoma and leukemia over several hours at 37 °C during apoptotic or necrotic killing of different cancer cells (K562, THP1, OCI-AML2, and TMD8). Additionally, we show that fura-10 is well suited to report Ca<sup>2+</sup> signals in intact murine pancreatic islets, another stress-sensitive cell preparation. Consequently, fura-10 is an optimal choice for measuring Ca²⁺ in primary human NK cells and other primary cell preparations.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"133 ","pages":"Article 103091"},"PeriodicalIF":4.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600390","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 : 2025-11-13DOI: 10.1016/j.ceca.2025.103090
Noemi Toth , Nordine Helassa , Martin Morad
Nuclear envelope (NE) is a double lipid bilayer separating the nucleus from the cytosol. While cytoplasmic and sarcoplasmic reticulum (SR) Ca2+ signaling is extensively studied, the role of NE in cellular Ca2+ dynamics and the identity and regulation of nuclear Ca2+ transporters remain less explored.
NE-associated Ca2+ activity was examined using a genetically engineered fluorescent Ca2+ probe targeting nuclear LaminB1 at the inner NE membrane in human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs). Confocal imaging of NE revealed larger and delayed but slower rise of Ca2+ in the nuclear lamina compared to ICa triggered cytosolic rise in Ca2+. Caffeine induced ∼4X larger Ca2+rise in NE lamina compared to ICa. To determine whether NE Ca2+ signaling depended on SR Ca2+ release, we measured the nuclear Ca2+signals of cells expressing genetically CICR-impaired RyR2 mutations (E3848A, Q3925E), where SR Ca2+ release was fully suppressed. In these CICR-deleted cells, although caffeine failed to activate robust NE Ca2+ transients, spontaneous beating persisted activating NE Ca2+ transients, suggesting Ca2+ signaling pathway remodeling and activation of an alternate Ca2+ pathway. Confocal imaging of hiPSCCMs infected with antibodies to Cx43 identified robust Cx43 expression in the NE, the inhibition of which by Gap19 protein blocked the rise of nuclear lamina Ca2+-transients. We conclude, that while SR Ca2+ release is essential in replenishing the NE Ca2+ content, RyR2 mutations that delete CICR induce remodeling of Ca2+signaling pathway that may include Cx43 to maintain Ca2+ fluxes critical for spontaneous beating and triggering of Ca2+transients.
{"title":"Connexin 43 as a novel Ca2+ transport pathway in the nuclear envelope of human induced pluripotent stem cell derived cardiomyocytes","authors":"Noemi Toth , Nordine Helassa , Martin Morad","doi":"10.1016/j.ceca.2025.103090","DOIUrl":"10.1016/j.ceca.2025.103090","url":null,"abstract":"<div><div>Nuclear envelope (NE) is a double lipid bilayer separating the nucleus from the cytosol. While cytoplasmic and sarcoplasmic reticulum (SR) Ca<sup>2+</sup> signaling is extensively studied, the role of NE in cellular Ca<sup>2+</sup> dynamics and the identity and regulation of nuclear Ca<sup>2+</sup> transporters remain less explored.</div><div>NE-associated Ca<sup>2+</sup> activity was examined using a genetically engineered fluorescent Ca<sup>2+</sup> probe targeting nuclear LaminB1 at the inner NE membrane in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC<img>CMs). Confocal imaging of NE revealed larger and delayed but slower rise of Ca<sup>2+</sup> in the nuclear lamina compared to I<sub>C</sub><sub>a</sub> triggered cytosolic rise in Ca<sup>2+</sup>. Caffeine induced ∼4X larger Ca<sup>2+</sup>rise in NE lamina compared to I<sub>C</sub><sub>a</sub>. To determine whether NE Ca<sup>2+</sup> signaling depended on SR Ca<sup>2+</sup> release, we measured the nuclear Ca<sup>2+</sup>signals of cells expressing genetically CICR-impaired RyR2 mutations (E3848A, Q3925E), where SR Ca<sup>2+</sup> release was fully suppressed. In these CICR-deleted cells, although caffeine failed to activate robust NE Ca<sup>2+</sup> transients, spontaneous beating persisted activating NE Ca<sup>2+</sup> transients, suggesting Ca<sup>2+</sup> signaling pathway remodeling and activation of an alternate Ca<sup>2+</sup> pathway. Confocal imaging of hiPSC<img>CMs infected with antibodies to Cx43 identified robust Cx43 expression in the NE, the inhibition of which by Gap19 protein blocked the rise of nuclear lamina Ca<sup>2+</sup>-transients. We conclude, that while SR Ca<sup>2+</sup> release is essential in replenishing the NE Ca<sup>2+</sup> content, RyR2 mutations that delete CICR induce remodeling of Ca<sup>2+</sup>signaling pathway that may include Cx43 to maintain Ca<sup>2+</sup> fluxes critical for spontaneous beating and triggering of Ca<sup>2+</sup>transients.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103090"},"PeriodicalIF":4.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573271","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 : 2025-11-01Epub Date: 2025-08-05DOI: 10.1016/j.ceca.2025.103066
Mélanie Robitaille
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.
{"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}
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