Pub Date : 2026-02-06DOI: 10.1016/j.ceca.2026.103124
Juan Alcalde, Ester Martín-Villar, Martin W Berchtold, Antonio Villalobo
{"title":"Corrigendum to: Ca<sup>2+</sup>/calmodulin-driven functions mediated by extracellular vesicles: a physiopathological perspective: [Cell Calcium 133 (2026)103105].","authors":"Juan Alcalde, Ester Martín-Villar, Martin W Berchtold, Antonio Villalobo","doi":"10.1016/j.ceca.2026.103124","DOIUrl":"https://doi.org/10.1016/j.ceca.2026.103124","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"103124"},"PeriodicalIF":4.0,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137484","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 : 2026-01-30DOI: 10.1016/j.ceca.2026.103125
Meiqin Tang, Ting Luo, Chunlan Kang, Feng Wang, Dongqing Yang, Ruili Cui, Chanjing Li, Yihan Zhang, Yiyao Liu, Min Li, Mei Hu, Ping Li
A-synuclein aggregation is a biomarker of Parkinson's disease (PD) whose feature is the progressive loss of dopaminergic neuron in the middle brain. The removal of a-synuclein aggregation through autophagy-lysosome pathway is a promising strategy for PD treatment. Transcription factor EB (TFEB) is a master regulator of autophagic and lysosomal biogenesis and function. Here, we report a library screen of intracellular Ca2+ inducers to identify small-molecule agonists of TFEB and discover MONNA can promote autophagic and lysosomal activity. Notably, MONNA facilitates the reduction of pathological a-synuclein in the Parkinson's disease model both in vitro and in vivo, and ameliorates PD-like behaviors in zebrafish. Mode of action studies reveal MONNA induces TFEB nuclear translocation through a Ca2+-dependent mechanism involving Calcineurin (CaN). Endoplasmic reticulum (ER) but not lysosome Ca2+ is critical to MONNA-induced TFEB activation and autophagy induction. Furthermore, Sarcoendoplasmic reticulum calcium ATPase (SERCA) pump of ER modulates TFEB nuclear translocation induced by MONNA. Our findings demonstrate that MONNA is the first ER Ca2+-dependent small synthetic TFEB agonist promoting the degradation of a-synuclein aggregates and alleviating Parkinson's disease. This ER Ca2+-Calcineurin-TFEB signaling pathway would broaden the way to develop drugs for PD.
a -synuclein聚集是帕金森病（PD）的生物标志物，其特征是中脑多巴胺能神经元的进行性丧失。通过自噬-溶酶体途径去除a-突触核蛋白聚集是一种很有前途的PD治疗策略。转录因子EB （TFEB）是自噬和溶酶体生物发生和功能的主要调节因子。在这里，我们报道了细胞内Ca2+诱导剂的文库筛选，以鉴定TFEB的小分子激动剂，并发现MONNA可以促进自噬和溶酶体活性。值得注意的是，MONNA在体外和体内均可促进帕金森病模型中病理a-突触核蛋白的减少，并改善斑马鱼的pd样行为。作用模式研究表明，MONNA通过钙调神经磷酸酶（Calcineurin, CaN）的Ca2+依赖机制诱导TFEB核易位。内质网（ER）而非溶酶体Ca2+对monna诱导的TFEB激活和自噬诱导至关重要。此外，内质网钙atp酶（SERCA）泵可调节MONNA诱导的TFEB核易位。我们的研究结果表明，MONNA是第一种ER Ca2+依赖性的小合成TFEB激动剂，可促进a-synuclein聚集体的降解并缓解帕金森病。这种ER Ca2+-钙调磷酸酶- tfeb信号通路将拓宽PD药物开发的途径。
{"title":"MONNA alleviates MPTP-induced Parkinson's disease in zebrafish by activating TFEB dependently on ER Calcium.","authors":"Meiqin Tang, Ting Luo, Chunlan Kang, Feng Wang, Dongqing Yang, Ruili Cui, Chanjing Li, Yihan Zhang, Yiyao Liu, Min Li, Mei Hu, Ping Li","doi":"10.1016/j.ceca.2026.103125","DOIUrl":"https://doi.org/10.1016/j.ceca.2026.103125","url":null,"abstract":"<p><p>A-synuclein aggregation is a biomarker of Parkinson's disease (PD) whose feature is the progressive loss of dopaminergic neuron in the middle brain. The removal of a-synuclein aggregation through autophagy-lysosome pathway is a promising strategy for PD treatment. Transcription factor EB (TFEB) is a master regulator of autophagic and lysosomal biogenesis and function. Here, we report a library screen of intracellular Ca<sup>2+</sup> inducers to identify small-molecule agonists of TFEB and discover MONNA can promote autophagic and lysosomal activity. Notably, MONNA facilitates the reduction of pathological a-synuclein in the Parkinson's disease model both in vitro and in vivo, and ameliorates PD-like behaviors in zebrafish. Mode of action studies reveal MONNA induces TFEB nuclear translocation through a Ca<sup>2+</sup>-dependent mechanism involving Calcineurin (CaN). Endoplasmic reticulum (ER) but not lysosome Ca<sup>2+</sup> is critical to MONNA-induced TFEB activation and autophagy induction. Furthermore, Sarcoendoplasmic reticulum calcium ATPase (SERCA) pump of ER modulates TFEB nuclear translocation induced by MONNA. Our findings demonstrate that MONNA is the first ER Ca<sup>2+</sup>-dependent small synthetic TFEB agonist promoting the degradation of a-synuclein aggregates and alleviating Parkinson's disease. This ER Ca<sup>2+</sup>-Calcineurin-TFEB signaling pathway would broaden the way to develop drugs for PD.</p>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"103125"},"PeriodicalIF":4.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118140","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 : 2026-01-22DOI: 10.1016/j.ceca.2026.103123
Yantao Zhang , Zhenxing Zhu , Piyao Ji , Yuyang Wu , Jianghua Ming , Yan Zhou
Osteoarthritis (OA) is a degenerative joint disorder strongly associated with senescence, involving pathological processes such as reactive oxygen species (ROS) accumulation and ferroptosis. Basic calcium phosphate (BCP) crystals are frequently found in the joints of OA patients, yet their role in OA pathogenesis remains poorly understood. Here, we aimed to investigate the role of synthetic BCP crystals in promoting OA progression and to elucidate the molecular mechanisms underlying senescence. In this study, a rat OA model was established by intra-articular injections of BCP crystals into the knee joint, and the effect of BCP crystals improving the ferroptosis phenotype of OA cartilage was investigated. Furthermore, the expression of senescence-related biomarkers and mitochondrial functions in BCP-treated chondrocytes was observed. Moreover, the role of synthetic BCP crystals in promoting ferroptosis process in chondrocytes was investigated, as well as their mechanism of action in OA, which was related to chondrocyte senescence. The in vivo findings demonstrated that BCP crystals accelerated cartilage senescence, worsened cartilage degradation, promoted osteophyte formation, and induced ferroptosis in the joint synovium. In vitro, BCP crystals intensified ferroptosis and oxidative stress in rat chondrocytes, increased ROS production, and further promoted mitochondrial dysfunction and chondrocyte senescence. Mechanistically, BCP crystals aggravated senescence-related pathological changes by inhibiting of the GPX4-NRF2 pathway and inducing ferroptosis, thereby promoting OA progression. Our findings demonstrate BCP crystals promote chondrocyte senescence by enhancing mitochondrial dysfunction and ferroptosis. This effect was mediated through downregulation of GPX4-NRF2 signaling, which provided a theoretical basis for exploring the pathogenesis and treatment of OA.
{"title":"Basic calcium phosphate crystals aggravate senescence-related osteoarthritis through GPX4-NRF2-mediated ferroptosis","authors":"Yantao Zhang , Zhenxing Zhu , Piyao Ji , Yuyang Wu , Jianghua Ming , Yan Zhou","doi":"10.1016/j.ceca.2026.103123","DOIUrl":"10.1016/j.ceca.2026.103123","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a degenerative joint disorder strongly associated with senescence, involving pathological processes such as reactive oxygen species (ROS) accumulation and ferroptosis. Basic calcium phosphate (BCP) crystals are frequently found in the joints of OA patients, yet their role in OA pathogenesis remains poorly understood. Here, we aimed to investigate the role of synthetic BCP crystals in promoting OA progression and to elucidate the molecular mechanisms underlying senescence. In this study, a rat OA model was established by intra-articular injections of BCP crystals into the knee joint, and the effect of BCP crystals improving the ferroptosis phenotype of OA cartilage was investigated. Furthermore, the expression of senescence-related biomarkers and mitochondrial functions in BCP-treated chondrocytes was observed. Moreover, the role of synthetic BCP crystals in promoting ferroptosis process in chondrocytes was investigated, as well as their mechanism of action in OA, which was related to chondrocyte senescence. The <em>in vivo</em> findings demonstrated that BCP crystals accelerated cartilage senescence, worsened cartilage degradation, promoted osteophyte formation, and induced ferroptosis in the joint synovium. <em>In vitro</em>, BCP crystals intensified ferroptosis and oxidative stress in rat chondrocytes, increased ROS production, and further promoted mitochondrial dysfunction and chondrocyte senescence. Mechanistically, BCP crystals aggravated senescence-related pathological changes by inhibiting of the GPX4-NRF2 pathway and inducing ferroptosis, thereby promoting OA progression. Our findings demonstrate BCP crystals promote chondrocyte senescence by enhancing mitochondrial dysfunction and ferroptosis. This effect was mediated through downregulation of GPX4-NRF2 signaling, which provided a theoretical basis for exploring the pathogenesis and treatment of OA.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"Article 103123"},"PeriodicalIF":4.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046170","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}
Microglia are the primary immune cells to sense and respond to all the pathological events in the brain. Voltage-gated proton channels (Hv1) are specifically expressed in the microglia to regulate their intracellular pH and contribute to redox homeostasis. Our previous work identified that S-023–0515 is a novel activator of microglial Hv1 channels, inducing neuroinflammation through unknown mechanisms. In this study, we demonstrate the direct binding of S-023–0515 onto the Hv1 channel using molecular docking, molecular dynamics (MD) simulations, and Bio-layer interferometry (BLI) techniques. Treatment with S-023–0515 induced a sustained intracellular alkalization, resulting in a gradual increase in cytosolic Ca2+ levels. None of the major plasma membrane Ca2+ ion channels, such as TRPV1, Cav1.2, ASIC and P2X7, nor intracellular Ca2+ release channels were found to be involved in S-023–0515-induced Ca2+ increase. This mobilisation of Ca2+ occurred through the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), as its inhibition annulled the S-023–0515-mediated Ca2+ rise. Hv1-mediated Ca²⁺ signaling further promoted NF-κB activation leading to a steady increase in proinflammatory cytokines, such as TNF-α and IL-1β, in BV-2 microglial cells, representing an inflammatory microglial phenotype. Notably, the proinflammatory response was solely attributable to Hv1 channel activation because neither NOX2 stimulation nor local cellular pH was altered following S-023–0515 treatment. Together, these findings suggest that NOX2-independent activation of Hv1 channels triggers a Hv1-SERCA-Ca2+-NF-κΒ signalling cascade, disrupting intracellular Ca2+ homeostasis and leading to microglial neurotoxicity.
{"title":"A NOX2-independent mechanism of Hv1 channel activation promotes inflammatory cytokine release from BV-2 microglia via intracellular Ca2+ mobilisation","authors":"Ashutosh Sharma , Priyanka Yadav , Shivani Yadav , Vikash Kumar , Kunvar Ravendra singh , Madhavi Ranawat , Shivani Pal , Ankita Yadav , Gokul Krishnan Nagendran , Sunil P. Kase , Yaduvender Yadav , Satish K. Mudedla , Valmik S. Shinde , Aravind Singh Kshatri","doi":"10.1016/j.ceca.2026.103122","DOIUrl":"10.1016/j.ceca.2026.103122","url":null,"abstract":"<div><div>Microglia are the primary immune cells to sense and respond to all the pathological events in the brain. Voltage-gated proton channels (Hv<sub>1</sub>) are specifically expressed in the microglia to regulate their intracellular pH and contribute to redox homeostasis. Our previous work identified that S-023–0515 is a novel activator of microglial Hv<sub>1</sub> channels, inducing neuroinflammation through unknown mechanisms. In this study, we demonstrate the direct binding of S-023–0515 onto the Hv<sub>1</sub> channel using molecular docking, molecular dynamics (MD) simulations, and Bio-layer interferometry (BLI) techniques. Treatment with S-023–0515 induced a sustained intracellular alkalization, resulting in a gradual increase in cytosolic Ca<sup>2+</sup> levels. None of the major plasma membrane Ca<sup>2+</sup> ion channels, such as TRPV1, Cav1.2, ASIC and P2X7, nor intracellular Ca<sup>2+</sup> release channels were found to be involved in S-023–0515-induced Ca<sup>2+</sup> increase. This mobilisation of Ca<sup>2+</sup> occurred through the sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase (SERCA), as its inhibition annulled the S-023–0515-mediated Ca<sup>2+</sup> rise. Hv<sub>1</sub>-mediated Ca²⁺ signaling further promoted NF-κB activation leading to a steady increase in proinflammatory cytokines, such as TNF-α and IL-1β, in BV-2 microglial cells, representing an inflammatory microglial phenotype. Notably, the proinflammatory response was solely attributable to Hv<sub>1</sub> channel activation because neither NOX2 stimulation nor local cellular pH was altered following S-023–0515 treatment. Together, these findings suggest that NOX2-independent activation of Hv<sub>1</sub> channels triggers a Hv<sub>1</sub>-SERCA-Ca<sup>2+</sup>-NF-κΒ signalling cascade, disrupting intracellular Ca<sup>2+</sup> homeostasis and leading to microglial neurotoxicity.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"Article 103122"},"PeriodicalIF":4.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046153","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}
Reticulocalbin1 (RCN1), a calcium-binding protein localized in the endoplasmic reticulum (ER), is implicated in cancer progression, but its role in the immune system remains poorly understood. To clarify the function of RCN1, we generated a RCN1-deficient (Rcn1−/−) mice using CRISPR-Cas9 system. Immunological characterization by flow cytometry revealed that while T cell populations in the spleen were unaffected, the proportion of CD8 single-positive (SP) thymocytes was significantly reduced in Rcn1−/− mice. In contrast, in vitro stimulation of splenic CD8+ T cells revealed no significant differences in the expression of cell surface activation markers or cytokines between Rcn1+/+ and Rcn1−/− mice. Functional analysis showed that at baseline, cytosolic calcium levels were significantly higher in Rcn1+/+ CD8+ T cells. In contrast, stimulus-induced calcium responses, including ER calcium release, extracellular calcium entry, and TCR-dependent calcium flux, were preserved in both genotypes. Collectively, our results suggest that RCN1 contributes to the fine-tuning of ER-associated calcium handling in naïve (non-activated) T cells, thereby modulating basal cytosolic calcium levels and supporting efficient thymic CD8⁺ T cell development.
{"title":"Reticulocalbin1-mediated regulation of calcium homeostasis in naïve T lymphoncytes","authors":"Takeru Kobayashi , Wooseok Seo , Norihisa Ichimura , Yusuke Urata , Hideharu Hibi , Hiroyoshi Nishikawa","doi":"10.1016/j.ceca.2026.103121","DOIUrl":"10.1016/j.ceca.2026.103121","url":null,"abstract":"<div><div>Reticulocalbin1 (RCN1), a calcium-binding protein localized in the endoplasmic reticulum (ER), is implicated in cancer progression, but its role in the immune system remains poorly understood. To clarify the function of RCN1, we generated a RCN1-deficient (<em>Rcn1<sup>−/−</sup></em>) mice using CRISPR-Cas9 system. Immunological characterization by flow cytometry revealed that while T cell populations in the spleen were unaffected, the proportion of CD8 single-positive (SP) thymocytes was significantly reduced in <em>Rcn1<sup>−/−</sup></em> mice. In contrast, <em>in vitro</em> stimulation of splenic CD8<sup>+</sup> T cells revealed no significant differences in the expression of cell surface activation markers or cytokines between <em>Rcn1<sup>+/+</sup></em> and <em>Rcn1<sup>−/−</sup></em> mice. Functional analysis showed that at baseline, cytosolic calcium levels were significantly higher in <em>Rcn1<sup>+/+</sup></em> CD8<sup>+</sup> T cells. In contrast, stimulus-induced calcium responses, including ER calcium release, extracellular calcium entry, and TCR-dependent calcium flux, were preserved in both genotypes. Collectively, our results suggest that RCN1 contributes to the fine-tuning of ER-associated calcium handling in naïve (non-activated) T cells, thereby modulating basal cytosolic calcium levels and supporting efficient thymic CD8⁺ T cell development.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"Article 103121"},"PeriodicalIF":4.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036035","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 : 2026-01-16DOI: 10.1016/j.ceca.2026.103119
Pedro Avelar , Tatiana P. Morais , Haissa de Castro-Abrantes , Adam Armada-Moreira , Joana Gonçalves-Ribeiro , Cláudia A. Valente , Ana Maria Sebastião , Maria José Diógenes , Sandra H. Vaz
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that, through the activation of its full length receptor, TrkB-FL, plays a pivotal role in neuroprotection, namely against neuronal toxicity mediated by amyloid-β peptide (Aβ). In astrocytes, the increase of calcium (Ca2+) signaling due the increase of metabotropic glutamate receptor type 5 (mGluR5) levels, induced by Aβ, has been considered deleterious for astrocytic function. In adition BDNF also increases intracellular calcium concentration ([Ca²⁺]ᵢ), in astrocytes, via activation of the truncated TrkB receptor isoform, TrkB-Tc. While the role of BDNF, in neurons, is well established, in terms of neuroprotection, its role in astrocytes, particularly in Aβ-induced toxicity conditions, remains less clear. Thus, this study aimed to evaluate the interplay between BDNF and Aβ in the modulation of [Ca2+]i signaling in primary cultures of cortical astrocytes.
Ca2+ transients were induced by the activation of mGluR5 through the application of its agonist DHPG. In astrocytes pre-exposed to Aβ25–35 (10 µM, for 48–72 h), the Ca2+ transient amplitude was significantly increased compared to the control. A similar increase was observed in astrocytes incubated for 48 h with BDNF (20 ng/mL), or when astrocytes were simultaneously exposed to BDNF and Aβ. The effect of BDNF was mediated by TrkB-Tc since it was prevented by a cocktail of the three siRNAs against TrkB-Tc expression. mGluR5 levels were significantly increased in astrocytes pre-exposed to Aβ, while exposure to BDNF did not affect mGluR5 levels. Importantly, while the presence of Aβ did affect TrkB-Tc receptor levels in astrocytes, the presence of BDNF prevented the increase in mGluR5 levels caused by Aβ thus precluding a further exacerbation of Ca2+ transients caused by Aβ.
{"title":"BDNF prevents amyloid-β-induced exacerbation of mGluR5-driven Ca2+ transients in astrocytes through TrkB-Tc activation","authors":"Pedro Avelar , Tatiana P. Morais , Haissa de Castro-Abrantes , Adam Armada-Moreira , Joana Gonçalves-Ribeiro , Cláudia A. Valente , Ana Maria Sebastião , Maria José Diógenes , Sandra H. Vaz","doi":"10.1016/j.ceca.2026.103119","DOIUrl":"10.1016/j.ceca.2026.103119","url":null,"abstract":"<div><div>Brain-derived neurotrophic factor (BDNF) is a neurotrophin that, through the activation of its full length receptor, TrkB-FL, plays a pivotal role in neuroprotection, namely against neuronal toxicity mediated by amyloid-β peptide (Aβ). In astrocytes, the increase of calcium (Ca<sup>2+</sup>) signaling due the increase of metabotropic glutamate receptor type 5 (mGluR5) levels, induced by Aβ, has been considered deleterious for astrocytic function. In adition BDNF also increases intracellular calcium concentration ([Ca²⁺]ᵢ), in astrocytes, via activation of the truncated TrkB receptor isoform, TrkB-Tc. While the role of BDNF, in neurons, is well established, in terms of neuroprotection, its role in astrocytes, particularly in Aβ-induced toxicity conditions, remains less clear. Thus, this study aimed to evaluate the interplay between BDNF and Aβ in the modulation of [Ca<sup>2+</sup>]<sub>i</sub> signaling in primary cultures of cortical astrocytes.</div><div>Ca<sup>2+</sup> transients were induced by the activation of mGluR5 through the application of its agonist DHPG. In astrocytes pre-exposed to Aβ<sub>25–35</sub> (10 µM, for 48–72 h), the Ca<sup>2+</sup> transient amplitude was significantly increased compared to the control. A similar increase was observed in astrocytes incubated for 48 h with BDNF (20 ng/mL), or when astrocytes were simultaneously exposed to BDNF and Aβ. The effect of BDNF was mediated by TrkB-Tc since it was prevented by a cocktail of the three siRNAs against TrkB-Tc expression. mGluR5 levels were significantly increased in astrocytes pre-exposed to Aβ, while exposure to BDNF did not affect mGluR5 levels. Importantly, while the presence of Aβ did affect TrkB-Tc receptor levels in astrocytes, the presence of BDNF prevented the increase in mGluR5 levels caused by Aβ thus precluding a further exacerbation of Ca<sup>2+</sup> transients caused by Aβ.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"Article 103119"},"PeriodicalIF":4.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035983","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 : 2026-01-11DOI: 10.1016/j.ceca.2026.103120
Punyadhara Pani , Diya Aich , Barsha Priyadarshini Kar , M. Shiwangi Giri , Gourabamani Swalsingh , Muthu Periasamy , Naresh Chandra Bal
Calsequestrin (CASQ) plays an important role in muscle contraction by buffering Ca2+ inside the sarcoplasmic reticulum (SR). Intriguingly, mammals express two CASQ isoforms encoded by separate genes with highly conserved protein structure. CASQ1 is mainly expressed in fast-twitch skeletal muscles; whereas CASQ2 predominates in slow-twitch muscles and heart. CASQ2 function is poorly defined in rhythmically beating heart where SR Ca2+-release is graded through Ca2+-induced Ca2+-release (CICR), compared to CASQ1 in skeletal muscle where Ca2+-release is all or none. A unique property of CASQ is that it can dynamically polymerize-depolymerize in Ca2+-concentration dependent manner. CASQ1 and CASQ2 not only differ in their polymerization properties but also interact with different RyR protein complexes at the junctional SR governing muscle fiber specific SR Ca2+-release. In recent years CASQ has gained renewed attention because mutations in CASQ1 and CASQ2 proteins cause cardiac and skeletal muscle disease, including malignant hyperthermia (skeletal muscle), cardiac arrhythmias and sudden cardiac death. Additionally studies have implicated that CASQ is more than a Ca2+-buffer and CASQ-dysfunction can affect mitochondrial function and Ca2+-entry via store operated Ca2+-entry. Therefore, the isoform specific functions of CASQ1 and CASQ2 in different striated muscles requires further investigation in the light of recent findings. This review explores what we have learned over last 30 years about CASQ and what gaps of knowledge still exist. Here, we discuss how structural divergence between CASQ1 and CASQ2, shape physio-pathological outcomes and highlight some of the recent findings that trigger renewed interest in CASQ proteins, including their role beyond Ca2+-buffering.
{"title":"Isoform-specific structure and function of calsequestrin: Implications beyond calcium buffering in health and disease","authors":"Punyadhara Pani , Diya Aich , Barsha Priyadarshini Kar , M. Shiwangi Giri , Gourabamani Swalsingh , Muthu Periasamy , Naresh Chandra Bal","doi":"10.1016/j.ceca.2026.103120","DOIUrl":"10.1016/j.ceca.2026.103120","url":null,"abstract":"<div><div>Calsequestrin (CASQ) plays an important role in muscle contraction by buffering Ca2+ inside the sarcoplasmic reticulum (SR). Intriguingly, mammals express two CASQ isoforms encoded by separate genes with highly conserved protein structure. CASQ1 is mainly expressed in fast-twitch skeletal muscles; whereas CASQ2 predominates in slow-twitch muscles and heart. CASQ2 function is poorly defined in rhythmically beating heart where SR Ca2+-release is graded through Ca2+-induced Ca2+-release (CICR), compared to CASQ1 in skeletal muscle where Ca2+-release is all or none. A unique property of CASQ is that it can dynamically polymerize-depolymerize in Ca2+-concentration dependent manner. CASQ1 and CASQ2 not only differ in their polymerization properties but also interact with different RyR protein complexes at the junctional SR governing muscle fiber specific SR Ca2+-release. In recent years CASQ has gained renewed attention because mutations in CASQ1 and CASQ2 proteins cause cardiac and skeletal muscle disease, including malignant hyperthermia (skeletal muscle), cardiac arrhythmias and sudden cardiac death. Additionally studies have implicated that CASQ is more than a Ca2+-buffer and CASQ-dysfunction can affect mitochondrial function and Ca2+-entry via store operated Ca2+-entry. Therefore, the isoform specific functions of CASQ1 and CASQ2 in different striated muscles requires further investigation in the light of recent findings. This review explores what we have learned over last 30 years about CASQ and what gaps of knowledge still exist. Here, we discuss how structural divergence between CASQ1 and CASQ2, shape physio-pathological outcomes and highlight some of the recent findings that trigger renewed interest in CASQ proteins, including their role beyond Ca2+-buffering.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"Article 103120"},"PeriodicalIF":4.0,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976066","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 : 2026-01-10DOI: 10.1016/j.ceca.2026.103118
Jujun Liu , Qingqing Hu , Keyi Sun , Huifang Tang , Xiaowei Qian
Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation and organ dysfunction. The Transient Receptor Potential Melastatin (TRPM) cation channels have recently emerged as dual-function modulators of various cellular processes, including bacterial clearance and inflammatory responses, which are crucial in the pathogenesis of sepsis. This review synthesizes current knowledge on the paradoxical roles of TRPM channels in septic pathophysiology, focusing on their expression and function in immune cells and other parenchymal organs, their contribution to immune dysregulation, and their potential as context-dependent therapeutic targets. By exploring the mechanisms through which TRPM channels mediate sepsis pathogenesis, this review provides insights into the challenges and opportunities for developing targeted therapeutic strategies for sepsis management.
{"title":"The dual role of transient receptor potential melastatin cation channels in sepsis","authors":"Jujun Liu , Qingqing Hu , Keyi Sun , Huifang Tang , Xiaowei Qian","doi":"10.1016/j.ceca.2026.103118","DOIUrl":"10.1016/j.ceca.2026.103118","url":null,"abstract":"<div><div>Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation and organ dysfunction. The Transient Receptor Potential Melastatin (TRPM) cation channels have recently emerged as dual-function modulators of various cellular processes, including bacterial clearance and inflammatory responses, which are crucial in the pathogenesis of sepsis. This review synthesizes current knowledge on the paradoxical roles of TRPM channels in septic pathophysiology, focusing on their expression and function in immune cells and other parenchymal organs, their contribution to immune dysregulation, and their potential as context-dependent therapeutic targets. By exploring the mechanisms through which TRPM channels mediate sepsis pathogenesis, this review provides insights into the challenges and opportunities for developing targeted therapeutic strategies for sepsis management.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"Article 103118"},"PeriodicalIF":4.0,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976067","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 : 2026-01-07DOI: 10.1016/j.ceca.2026.103117
Zi-Yang Huang , Yu-Yun Zhou , Xin-Ni Sun , Yi-Ran Ye , Fei-Fei Huang , Jie Sheng , Dan-Yang Zou , Ting-Ting Tang , Zi-Ying Yang , Tong-Zhen Weng , Xin-Rui Ling-Hu , Wai Hou Tang , Yun-Xin Zhu , Lei Chen , Su Qu , Wen-Liang Zhou , Yi-Lin Zhang
The epididymis establishes a unique hyper-potassium luminal microenvironment essential for sperm maturation and storage, which is largely orchestrated by epididymal epithelial ion transport. Although the transient receptor potential melastatin 8 (TRPM8) is broadly expressed across various organ systems, its physiological role in male reproduction has remained largely unexplored. This study demonstrated that TRPM8 was predominantly expressed in rat epididymal epithelial cells. Activation of TRPM8 by either the exogenous agonist WS-12 or the endogenous hormone testosterone triggered a decrease in short-circuit current (ISC) response in primary cultured rat epididymal epithelial cells. This ISC response was suppressed by removal of extracellular K+ or by pharmacological inhibition of Ca2+-activated potassium channels (KCa), Na+-K+ ATPase or the Na+-K+-Cl− cotransporter, indicating that TRPM8 mediated transepithelial K+ secretion in a Ca2+-dependent manner. Consistently, TRPM8 activation increased intracellular Ca2+ concentration in primary rat epididymal epithelial cells, which could be abolished by the removal of extracellular Ca2+. An in vivo study showed functional TRPM8 deficiency disrupted the luminal hyper-potassium microenvironment in rat epididymis. Moreover, impaired sperm motility and reduced male fertility were observed in TRPM8-deficient rats, which could be rescued by restoring luminal hyper-potassium microenvironment through KCa activation. Overall, this study elucidates a crucial role for TRPM8 in establishing the epididymal hyper-potassium microenvironment, offering valuable insights into the physiological function of TRPM8 in male reproductive health and disease.
{"title":"Activation of TRPM8 promotes K+ secretion in rat epididymal epithelium","authors":"Zi-Yang Huang , Yu-Yun Zhou , Xin-Ni Sun , Yi-Ran Ye , Fei-Fei Huang , Jie Sheng , Dan-Yang Zou , Ting-Ting Tang , Zi-Ying Yang , Tong-Zhen Weng , Xin-Rui Ling-Hu , Wai Hou Tang , Yun-Xin Zhu , Lei Chen , Su Qu , Wen-Liang Zhou , Yi-Lin Zhang","doi":"10.1016/j.ceca.2026.103117","DOIUrl":"10.1016/j.ceca.2026.103117","url":null,"abstract":"<div><div>The epididymis establishes a unique hyper-potassium luminal microenvironment essential for sperm maturation and storage, which is largely orchestrated by epididymal epithelial ion transport. Although the transient receptor potential melastatin 8 (TRPM8) is broadly expressed across various organ systems, its physiological role in male reproduction has remained largely unexplored. This study demonstrated that TRPM8 was predominantly expressed in rat epididymal epithelial cells. Activation of TRPM8 by either the exogenous agonist WS-12 or the endogenous hormone testosterone triggered a decrease in short-circuit current (<em>I</em><sub>SC</sub>) response in primary cultured rat epididymal epithelial cells. This <em>I</em><sub>SC</sub> response was suppressed by removal of extracellular K<sup>+</sup> or by pharmacological inhibition of Ca<sup>2+</sup>-activated potassium channels (K<sub>Ca</sub>), Na<sup>+</sup>-K<sup>+</sup> ATPase or the Na<sup>+</sup>-K<sup>+</sup>-Cl<sup>−</sup> cotransporter, indicating that TRPM8 mediated transepithelial K<sup>+</sup> secretion in a Ca<sup>2+</sup>-dependent manner. Consistently, TRPM8 activation increased intracellular Ca<sup>2+</sup> concentration in primary rat epididymal epithelial cells, which could be abolished by the removal of extracellular Ca<sup>2+</sup>. An <em>in vivo</em> study showed functional TRPM8 deficiency disrupted the luminal hyper-potassium microenvironment in rat epididymis. Moreover, impaired sperm motility and reduced male fertility were observed in TRPM8-deficient rats, which could be rescued by restoring luminal hyper-potassium microenvironment through K<sub>Ca</sub> activation. Overall, this study elucidates a crucial role for TRPM8 in establishing the epididymal hyper-potassium microenvironment, offering valuable insights into the physiological function of TRPM8 in male reproductive health and disease.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"134 ","pages":"Article 103117"},"PeriodicalIF":4.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957837","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 : 2026-01-03DOI: 10.1016/j.ceca.2026.103108
Bowen Lyu, Jiachen Lin, Lunhao Chen, Yue Wang
The transient receptor potential vanilloid 4 (TRPV4) ion channel is a pivotal regulator of calcium homeostasis, with its pleiotropic functions being increasingly elucidated across diverse physiological systems. Emerging evidence now underscores its indispensable role within the skeletal system, where it transduces multifaceted stimuli-notably mechanical loading and osmotic stress-into precise calcium signals that orchestrate skeletal development and homeostasis across various cell lineages. Pathogenic mutations in TRPV4 disrupt this critical signaling, giving rise to a broad spectrum of skeletal dysplasias and revealing distinct genotype-phenotype correlations. This review systematically integrates contemporary insights into the mechanistic actions of TRPV4 in osteoblasts, chondrocytes, and other skeletal cell types, delineating how specific mutations culminate in defined skeletal pathologies. Furthermore, we catalog established and emerging pharmacological modulators of TRPV4 and critically evaluate their potential within the therapeutic pipeline for skeletal dysplasia.
{"title":"The emerging role of TRPV4 in skeletal biology: Mechanotransduction, mutation, and therapeutic potential.","authors":"Bowen Lyu, Jiachen Lin, Lunhao Chen, Yue Wang","doi":"10.1016/j.ceca.2026.103108","DOIUrl":"https://doi.org/10.1016/j.ceca.2026.103108","url":null,"abstract":"<p><p>The transient receptor potential vanilloid 4 (TRPV4) ion channel is a pivotal regulator of calcium homeostasis, with its pleiotropic functions being increasingly elucidated across diverse physiological systems. Emerging evidence now underscores its indispensable role within the skeletal system, where it transduces multifaceted stimuli-notably mechanical loading and osmotic stress-into precise calcium signals that orchestrate skeletal development and homeostasis across various cell lineages. Pathogenic mutations in TRPV4 disrupt this critical signaling, giving rise to a broad spectrum of skeletal dysplasias and revealing distinct genotype-phenotype correlations. This review systematically integrates contemporary insights into the mechanistic actions of TRPV4 in osteoblasts, chondrocytes, and other skeletal cell types, delineating how specific mutations culminate in defined skeletal pathologies. Furthermore, we catalog established and emerging pharmacological modulators of TRPV4 and critically evaluate their potential within the therapeutic pipeline for skeletal dysplasia.</p>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":" ","pages":"103108"},"PeriodicalIF":4.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965216","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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