Cell calcium最新文献

{"title":"LETM1 and mitochondrial calcium homeostasis: A controversial but critical role in cellular function and disease","authors":"Guilherme Rodrigo RM dos Santos ,&nbsp;Maiara Ingrid Cavalcante Queiroz ,&nbsp;Ana Catarina Rezende Leite","doi":"10.1016/j.ceca.2025.103085","DOIUrl":"10.1016/j.ceca.2025.103085","url":null,"abstract":"<div><div>Calcium is a pivotal ion in cellular signaling, orchestrating pathways that support both cell survival and cell death. The mitochondria and endoplasmic reticulum are the principal organelles responsible for Ca²⁺ storage and play fundamental roles in maintaining intracellular Ca²⁺ homeostasis. The mitochondrial outer membrane (MOM) acts as a selective barrier that regulates the exchange of metabolites and other essential molecules necessary for mitochondrial function. This tightly regulated exchange depends on specific proteins, such as the voltage-dependent anion channel (VDAC), which serves as a key mediator of metabolite flux across the MOM. The mitochondrial Ca²⁺ uniporter (MCU) and the electrogenic Na⁺/Li⁺/Ca²⁺ exchanger (NCLX) represents the best-characterized mechanisms governing mitochondrial Ca²⁺ uptake and efflux, respectively. The leucine zipper EF-hand–containing transmembrane protein 1 (LETM1), localized to the inner mitochondrial membrane (IMM), has also been implicated in the regulation of mitochondrial Ca²⁺ homeostasis. This IMM protein was initially identified in association with Wolf–Hirschhorn Syndrome (WHS), a rare chromosomal disorder characterized by microcephaly, growth retardation, intellectual disability, and early-onset epileptic seizures. Approximately sixteen years ago, LETM1 was proposed to mediate K⁺/H⁺ exchange across the IMM. However, subsequent studies suggested an alternative function as a Ca²⁺/H⁺ exchanger, leading to an ongoing debate regarding its exact physiological role. Despite this controversy, the crucial contribution of LETM1 to mitochondrial physiology is widely acknowledged. LETM1 is considered an essential gene, and its dysfunction has been associated with a spectrum of pathological conditions, including Parkinson’s disease, obesity, and cancer.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103085"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transglutaminase 2 controls calcium dependent mitochondrial dysfunction and fibroblast senescence by repressing PIEZO2","authors":"Jiaxiao Chen ,&nbsp;Geyan Tian ,&nbsp;Ming Hua ,&nbsp;Min Gu ,&nbsp;Wentao Sun ,&nbsp;Jingyi Xu ,&nbsp;Changjiao Luan ,&nbsp;Juping Chen ,&nbsp;Jiaxin Shi ,&nbsp;Yinsong Chen ,&nbsp;Xingjie Ma","doi":"10.1016/j.ceca.2025.103088","DOIUrl":"10.1016/j.ceca.2025.103088","url":null,"abstract":"<div><div>Calcium and intracellular calcium signaling have emerged as critical mediators of cellular senescence. However, the mechanisms by which calcium signaling participates in the regulation of senescence remain only partially understood. In this study, we identified that Transglutaminase 2 (TGM2) is remarkably upregulated in response to senescence stimuli. Furthermore, TGM2 overexpression accelerated fibroblast senescence, as evidenced by the upregulation of p16, p21, increased senescence associated β-galactosidase (SA-β-Gal) activity, decreased cell proliferative capacity and induction of senescence-associated secretory phenotype (SASP), whereas the silencing of TGM2 staved off the senescent phenotype of fibroblasts induced by therapy. Mechanistically, TGM2 facilitates mitochondrial calcium accumulation, thereby contributing to mitochondrial dysfunction, activation of cGAS-STING signaling and ultimately leading to fibroblast cellular senescence. Furthermore, RNA-sequencing of senescent cells containing siRNA control or siRNA against TGM2 revealed that TGM2 triggers fibroblast senescence by repressing mechanosensitive ion channel PIEZO2. Interestingly, knockdown of PIEZO2 counteracted the effect of TGM2 repression on inhibiting cGAS-STING signaling and delaying cellular senescence. Taken together, our findings demonstrate that TGM2 serves as a key regulator of fibroblast senescence by modulating calcium dependent mitochondrial dysfunction and provide potential therapeutical targets for combating aging process and age-associated disorders.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103088"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of actin cytoskeleton by Ca2+-binding S100 proteins","authors":"Ewelina Jurewicz ,&nbsp;Joanna Moraczewska ,&nbsp;Anna Filipek","doi":"10.1016/j.ceca.2025.103087","DOIUrl":"10.1016/j.ceca.2025.103087","url":null,"abstract":"<div><div>The actin cytoskeleton is a dynamic network present in all eukaryotic cells. It plays a central role in various cellular processes, including cell shape maintenance, motility, intracellular transport, and cell division. The actin cytoskeleton consists of actin filaments and a diverse array of associated actin-binding proteins (ABPs), which regulate the assembly, organization, and functions of actin filaments. S100 proteins, a family of low-molecular-weight Ca²⁺-binding proteins, have emerged as important regulators of actin filaments. They exert their regulatory functions either directly, through interactions with actin and actin-binding proteins (ABPs), or indirectly, by modulating Ca²⁺ release and thereby influencing actin-dependent contractility. This review article provides a comprehensive overview of current literature on the S100-dependent regulation of actin cytoskeleton dynamics in diverse cellular contexts. Specifically, it highlights the role of S100 proteins in modulating striated muscle contractility, actin–myosin interactions in smooth muscle, mechanotransduction, stress fiber assembly, lamellipodia formation, actin cortex organization, and structural organization of the actin cytoskeleton within synapses.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103087"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial PIEZO1 activation impairs osteogenesis via GREM1-mediated inhibition of BMP signaling","authors":"Haoran Zhang ,&nbsp;Bowen Wang ,&nbsp;Jing He ,&nbsp;Shengyi Zhou ,&nbsp;Juan Song ,&nbsp;Ziwen Liu ,&nbsp;Xiangyu Zeng ,&nbsp;Ying Xing ,&nbsp;Feng Guo ,&nbsp;Jianyu Liu","doi":"10.1016/j.ceca.2025.103084","DOIUrl":"10.1016/j.ceca.2025.103084","url":null,"abstract":"<div><h3>Aim</h3><div>To investigate the effects and underlying mechanisms of systemic PIEZO1 activation on the bone vasculature and osteogenesis.</div></div><div><h3>Methods</h3><div>Three-week-old C57BL/6J male mice were intraperitoneally injected with Yoda1, and changes in bone microstructure and vasculature were assessed via micro-CT and immunofluorescence. MC3T3-E1 osteoprogenitors and endothelial cells (human umbilical vein endothelial cells, HUVECs and human bone marrow microvascular endothelial cells, hBMECs) were treated with Yoda1 in vitro. Gene expression analysis, alkaline phosphatase (ALP) assays, and RNA sequencing were performed to assess osteogenic activity and endothelial identity, respectively. Alterations in the osteogenic-promoting function of endothelial cells upon PIEZO1 activation were evaluated by treating MC3T3-E1 cells with endothelial-conditioned media.</div></div><div><h3>Results</h3><div>Systemic Yoda1 administration reduced the abundance of CD31^hiEMCN^hi-type H vessels and disrupted trabecular bone microarchitecture. Yoda1 suppressed osteogenic gene expression and ALP activity in MC3T3-E1 cells, even at low concentrations. RNA-seq of Yoda1-treated hBMECs revealed a transcriptional shift toward an <span>l</span>-type endothelial phenotype and upregulation of the expression of BMP antagonists, including GREM1. Functional rescue assays confirmed that endothelial-derived GREM1 inhibits BMP4-induced osteogenic differentiation via paracrine signaling.</div></div><div><h3>Conclusion</h3><div>Our study reveals a dual role of PIEZO1 in bone biology, demonstrating that its activation disrupts vascular–osteogenic coupling and suppresses osteoblast differentiation through the PIEZO1–GREM1–BMP4 axis. These findings suggest that caution should be taken when targeting PIEZO1 for bone regeneration and highlight the importance of dose and duration in therapeutic applications.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103084"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CNO induced Ca2+ store and glutamate-dependent nonspecific Ca2+ signalling in DREADD-free brain slices","authors":"Xiao-Yu Zhang ,&nbsp;Xi Wu ,&nbsp;Rui-yun Bi ,&nbsp;Shan Zhang ,&nbsp;Ye-Hua Gan","doi":"10.1016/j.ceca.2025.103070","DOIUrl":"10.1016/j.ceca.2025.103070","url":null,"abstract":"<div><div>DREADD (design receptors exclusively activated by designer drugs) is a widely used powerful tool designed to study specific cellular functions. However, off-target effects of chemogenetic activators, including clozapine N-oxide (CNO) and deschloroclozapine (DCZ), have been reported. In our study, we demonstrated the direct off-target effects of CNO and DCZ on basal Ca²⁺ levels in the locus coeruleus nucleus in both neurons and astrocytes by combining viral microinjection, Ca²⁺ imaging and electrophysiology. We observed that CNO induced a Ca²⁺ store-dependent increase in basal Ca²⁺ in both DREADD-absent neurons and astrocytes; interestingly, CNO directly increased the frequency of spontaneous presynaptic glutamate release. Furthermore, ionotropic glutamate receptors contributed to the CNO-induced increase in Ca²⁺ in both DREADD-free neurons and astrocytes. Importantly, IP3R2-KO diminished CNO-induced Ca²⁺ raise in astrocytes but not neurons. Our results revealed direct Ca²⁺ store- and glutamate-dependent off-target effects of DREADD agonists during their cellular action, which may help elucidate the mechanisms underlying the off-target effects of chemogenetic tools.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103070"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dantrolene normalizes heightened Ca2+ influx in activated T cells from the familial Alzheimer's disease TgF344-AD rats","authors":"Navdeep K. Uppal ,&nbsp;Anthony Valenzuela ,&nbsp;Pamela J. Lein ,&nbsp;Alla F. Fomina","doi":"10.1016/j.ceca.2025.103072","DOIUrl":"10.1016/j.ceca.2025.103072","url":null,"abstract":"<div><h3>Aim</h3><div>Dysregulation of the peripheral immune response contributes to Alzheimer's disease pathogenesis. Dantrolene, a negative allosteric modulator of ryanodine receptor types 1 and 3, reduces neurodegeneration in Alzheimer's disease animal models by an unclear mechanism. Given that Alzheimer's disease causative mutations in amyloid precursor and presenilin proteins interfere with intracellular Ca²⁺ signaling in neurons, we tested the hypotheses that these mutations may impair Ca²⁺ signaling in T lymphocytes and that dantrolene can repair this defect.</div></div><div><h3>Methods</h3><div>We explored cytosolic Ca²⁺ dynamics and effects of dantrolene sodium in resting and activated splenic T cells derived from adult transgenic TgF344-AD rats expressing mutant human \"Swedish\" amyloid precursor (APPsw) and presenilin 1 lacking exon 9 (PS1Δ9) proteins, and in control wild-type rats.</div></div><div><h3>Results</h3><div>We found no differences in the cytosolic Ca²⁺ signaling between resting T cells from TgF344-AD and control rats. In contrast, amplitudes of caffeine-triggered calcium transients and store-operated Ca²⁺ entry were significantly larger in activated TgF344-AD rat T cells relative to wild-type rat T cells. Preincubation with dantrolene sodium reduced the amplitude and the rate of Ca²⁺ influx in activated TgF344-AD rat T cells in the absence of store refilling and after dissipation of inner mitochondrial membrane potential, indicating that it does not involve Ca²⁺ release via ryanodine receptors or mitochondrial Ca²⁺ uptake.</div></div><div><h3>Conclusions</h3><div>Expression of Alzheimer's disease risk genes upregulates the store-operated Ca²⁺ entry in T cells, which may alter peripheral immune responses and exacerbate Alzheimer's disease pathogenesis. We speculate that dantrolene's neuroprotective effect in Alzheimer's disease animal models may be due to its normalization of the peripheral T cells' Ca²⁺ signaling and functions.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103072"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium homeostasis in trypanosomatids: A review of molecular targets and inhibitors","authors":"Natália Caroline Costa Coelho ,&nbsp;Angela Maria Arenas Velásquez ,&nbsp;Jhonatan Santos de Lima ,&nbsp;Ana Laura Dias Ramos ,&nbsp;Eduardo Maffud Cilli ,&nbsp;Marcia A.S. Graminha","doi":"10.1016/j.ceca.2025.103086","DOIUrl":"10.1016/j.ceca.2025.103086","url":null,"abstract":"<div><div>Calcium ion (Ca²⁺) signaling plays a pivotal role in the survival, differentiation, and virulence of trypanosomatids, including <em>Leishmania</em> spp., <em>Trypanosoma brucei</em>, and <em>Trypanosoma cruzi</em>, making it an attractive therapeutic target. This review integrates current knowledge on Ca²⁺ homeostasis in these parasites, addressing the plasma membrane, endoplasmic reticulum (ER), acidocalcisomes, mitochondria, lysosomes, and other organelles, with particular emphasis on key transporters and signaling pathways. In addition, we summarize genetic and pharmacological strategies used to validate Ca²⁺-related targets and highlight recent advances in both repurposed and novel compounds that disrupt Ca²⁺ homeostasis in trypanosomatids.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103086"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin 43 as a novel Ca2+ transport pathway in the nuclear envelope of human induced pluripotent stem cell derived cardiomyocytes","authors":"Noemi Toth ,&nbsp;Nordine Helassa ,&nbsp;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) 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.</div><div>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 (hiPSC<img>CMs). Confocal imaging of NE revealed larger and delayed but slower rise of Ca²⁺ in the nuclear lamina compared to I_C_a triggered cytosolic rise in Ca²⁺. Caffeine induced ∼4X larger Ca²⁺rise in NE lamina compared to I_C_a. 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 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 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.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103090"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","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}

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

{"title":"Neuronal regulation of myenteric interstitial cells of Cajal (ICC-MY) in the proximal colon","authors":"Salah A. Baker ,&nbsp;Bernard T. Drumm ,&nbsp;Manushri Karwa ,&nbsp;Katy M. Thompson ,&nbsp;Benjamin Smith ,&nbsp;Kenton M. Sanders","doi":"10.1016/j.ceca.2025.103082","DOIUrl":"10.1016/j.ceca.2025.103082","url":null,"abstract":"<div><div>Interstitial cells of Cajal (ICC) generate contractile patterns of colonic motility. We investigated innervation of ICC within the plane of the myenteric plexus (ICC-MY) in proximal colon using mice expressing GCaMP6f in ICC. ICC-MY generated localized Ca²⁺ transients that couple to activation of ANO1 channels, a Ca²⁺-activated Cl^- conductance. ICC are electrically coupled to SMCs, so activation or suppression of currents in ICC affects excitability of SMCs. ICC-MY displayed tonic inhibition, as the neurotoxin, TTX, increased the frequency of Ca²⁺ transients. Tonic inhibition was mimicked by a nitric oxide donor, NONOate, and by a guanylate cyclase agonist (Bay 58–2667). In contrast ODQ mimicked effects of TTX, increasing Ca²⁺ transients. Carbachol (CCh) increased Ca²⁺ transients in ICC-MY, and these effects were mediated by M3 muscarinic receptors. Neostigmine, also increased Ca²⁺ transients, suggesting there is tonic activation of enteric excitatory neurons in colonic muscles. Substance P and antagonists of NK1 and NK2 receptors had no effect on Ca²⁺ transients in ICC-MY. Electrical field stimulation (EFS), under conditions that emphasized excitatory neural responses, enhanced Ca²⁺ transients, and these effects were blocked by atropine or an M3 receptor antagonist (DAU 5884). EFS in the presence of atropine caused inhibition of Ca²⁺ via release of NO. Cessation of nitrergic stimulation resulted in a substantial increase in Ca²⁺ transients, known as post-stimulus excitation. In summary, ICC-MY, important for the generation of propulsive contractions in the colon, are innervated by excitatory (cholinergic) and inhibitory (nitrergic) motor neurons, and these inputs regulate the excitability of these cells.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103082"},"PeriodicalIF":4.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154986","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}