Plant calmodulins(CaMs)and calmodulin-like proteins(CMLs)mediate Ca~(2+)signaling in response to abiotic stresses.Manipulation of this signaling in crops could increase stress tolerance.We review methods for detecting...Plant calmodulins(CaMs)and calmodulin-like proteins(CMLs)mediate Ca~(2+)signaling in response to abiotic stresses.Manipulation of this signaling in crops could increase stress tolerance.We review methods for detecting Ca~(2+)signals,regulatory roles of Ca Ms and CMLs,binding targets,and Ca~(2+)networks under abiotic stress in organelles.展开更多
Mitochondrial calcium uniporter(MCU)is a conserved calcium ion(Ca^(2+))transporter in the mitochondrial inner membrane of eukaryotic cells.How MCU proteins regulate Ca^(2+)flow and modulate plant cell development rema...Mitochondrial calcium uniporter(MCU)is a conserved calcium ion(Ca^(2+))transporter in the mitochondrial inner membrane of eukaryotic cells.How MCU proteins regulate Ca^(2+)flow and modulate plant cell development remain largely unclear.Here,we identified the gene GhMCU4 encoding a MCU protein that negatively regulates plant development and fiber elongation in cotton(Gossypium hirsutum).GhMCU4expressed constitutively in various tissues with the higher transcripts in elongating fiber cells.Knockdown of GhMCU4 in cotton significantly elevated the plant height and root length.The calcium signaling pathway was significantly activated and calcium sensor genes,including Ca^(2+)dependent modulator of interactor of constitutively active ROP(GhCMI1),calmodulin like protein(GhCML46),calciumdependent protein kinases(GhCPKs),calcineurin B-like protein(GhCBLs),and CBL-interacting protein kinases(GhCIPKs),were dramatically upregulated in GhMCU4-silenced plants.Metabolic processes were preferentially enriched,and genes related to regulation of transcription were upregulated in GhMCU4-silenced plants.The contents of Ca^(2+)and H_(2)O_(2)were significantly increased in roots and leaves of GhMCU4-silenced plants.Fiber length and Ca^(2+)and H_(2)O_(2)contents in fibers were significantly increased in GhMCU4-silenced plants.This study indicated that GhMCU4 plays a negative role in regulating cell elongation in cotton,thus expanding understanding in the role of MCU proteins in plant growth and development.展开更多
Background:Kai-Xin-San,a classical Chinese medicine prescription,has been widely applied in the clinical therapy for depression,but its pharmacological mechanism remains to be further explored.Based on network pharmac...Background:Kai-Xin-San,a classical Chinese medicine prescription,has been widely applied in the clinical therapy for depression,but its pharmacological mechanism remains to be further explored.Based on network pharmacology,molecular docking and animal experiments,the research is performed to exploit pharmacological mechanism of Kai-Xin-San for treating depression.Methods:Obtain chemical components and potential targets of Kai-Xin-San through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,Encyclopedia of Traditional Chinese Medicine and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine databases,and then screen the active ingredients of each herb in accordance with absorption,distribution,metabolism,and excretion.The GenCards,Online Mendelian Inheritance in Man,Therapeutic Target database and DrugBank databases were used to obtain the major targets of depression,and the STRING platform was used to construct the protein-protein interaction network and explore the potential protein functional modules in the network.The targets were subjected to Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis by STRING database and Metascape database.The interaction network of“Kai-Xin-San active components-depression-targets-pathways”was constructed by Cytoscape,and molecular docking verification was performed by Auto Dock tools.Finally,animal experiments were carried out for further verification.The chronic restraint stress depression model was established and mice were randomly divided into 4 groups:control group,chronic restraint stress group,fluoxetine group and Kai-Xin-San group.Behavioral tests were used to evaluate the depressive phenotype of mice.The expression of CaMKII-,synaptophysin,poststroke depression-95,and CACNA1C were all detected using a western blot.Results:Network analysis shows that Kai-Xin-San may mainly regulate calcium signaling pathway to exert antidepressant effects.A majority of the targets and components have good binding activity,according to the molecular docking studies.In the current study,behavioral tests showed that Kai-Xin-San could effectively alleviate depression-like behaviors in mice compared with the chronic restraint stress group,which effect was comparable to fluoxetine.Meanwhile,compared with the chronic restraint stress group,protein levels of CACNA1C,CaMKII-α,synaptophysin and poststroke depression-95 were significantly increased(P<0.05).Conclusion:The research initially identifies the multi-component,multi-target,and multi-path mechanism of Kai-Xin-San in the treatment of depression.Kai-Xin-San may improve synaptic plasticity through calcium signaling pathway to exert antidepressant effects.展开更多
Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy. The pathogenesis of pancreatitis is still not well understood. Calcium (Ca<sup>2+</sup>) is a versatile ca...Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy. The pathogenesis of pancreatitis is still not well understood. Calcium (Ca<sup>2+</sup>) is a versatile carrier of signals regulating many aspects of cellular activity and plays a central role in controlling digestive enzyme secretion in pancreatic acinar cells. Ca<sup>2+</sup> overload is a key early event and is crucial in the pathogenesis of many diseases. In pancreatic acinar cells, pathological Ca<sup>2+</sup> signaling (stimulated by bile, alcohol metabolites and other causes) is a key contributor to the initiation of cell injury due to prolonged and global Ca<sup>2+</sup> elevation that results in trypsin activation, vacuolization and necrosis, all of which are crucial in the development of pancreatitis. Increased release of Ca<sup>2+</sup> from stores in the intracellular endoplasmic reticulum and/or increased Ca<sup>2+</sup> entry through the plasma membrane are causes of such cell damage. Failed mitochondrial adenosine triphosphate (ATP) production reduces re-uptake and extrusion of Ca<sup>2+</sup> by the sarco/endoplasmic reticulum Ca<sup>2+</sup>-activated ATPase and plasma membrane Ca<sup>2+</sup>-ATPase pumps, which contribute to Ca<sup>2+</sup> overload. Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca<sup>2+</sup> signals in pancreatitis. The lack of available specific treatments is therefore an objective of ongoing research. Research is currently underway to establish the mechanisms and interactions of Ca<sup>2+</sup> signals in the pathogenesis of pancreatitis.展开更多
Calcium ions （Ca2＋） act as an intracellular second messenger and affect nearly all aspects of cellular life. They are functioned by interacting with polar auxin transport, and the negative phototropism of plant roo...Calcium ions （Ca2＋） act as an intracellular second messenger and affect nearly all aspects of cellular life. They are functioned by interacting with polar auxin transport, and the negative phototropism of plant roots is caused by the transport of auxin from the irradiated side to the shaded side of the roots. To clarify the role of calcium signaling in the modulation of rice root negative phototropism, as well as the relationship between polar auxin transport and calcium signaling, calcium signaling reagents were used to treat rice seminal roots which were cultivated in hydroculture and unilaterally illuminated at an intensity of 100-200 pmol/（m2.s） for 24 h. Negative phototropism curvature and growth rate of rice roots were both promoted by exogenous CaCI2 lower than 100 pmol/L, but inhibited by calcium channel blockers （verapamil and LaCI3）, calcineurin inhibitor （chlorpromazine, CPZ）, and polar auxin transport inhibitor （N-l-naphthylphthalamic acid, NPA）. Roots stopped growing and negative phototropism disappeared when the concentrations increased to 100 pmol/L verapamil, 12.500 ~Jmol/L LaCI3, 60 pmol/L CPZ, and 6 pmol/L NPA. Moreover, 100 pmol/L CaCI2 could relieve the inhibition of LaCI3, verapamil and NPA. The enhanced negative phototropism curvature was caused by the transportation of more auxin from the irradiated side to the shaded side in the presence of exogenous Ca2＋. Calcium signaling plays a key role as a second messenger in the process of light signal regulation of rice root growth and negative phototropism.展开更多
The potential involvement of calcium in signalling in cyanobacteria has been investigated in recent years. Enough evidences showed that the cyanobacteria were capable of sensing and distinguishing different environmen...The potential involvement of calcium in signalling in cyanobacteria has been investigated in recent years. Enough evidences showed that the cyanobacteria were capable of sensing and distinguishing different environmental stimuli, and making responses in ways of Ca^2＋ transients, which were the results of influx or efflux of Ca^2＋ aroused by different environmental stimuli. The calcium signal elicited by nitrogen starvation was crucial to heterocyst differentiation in filamentous cyanobacteria Anabaena species. Identification of a calcium-binding protein （CcbP） from Anabaena sp. PCC 7120 provided further evidence, and the degradation and down-regulation of CcbP accounted for the generation of calcium signal when nitrogen starvation exits. However, the encoding and decoding mechanisms of the calcium signals in cyanobacteria still remain unclear. In order to reveal the exact role of it, a detailed, systematic investigation will be needed, especially for the calcium dynamics at the single cell level.展开更多
Exosomes are small membrane vesicles containing microRNA,RNA,DNA fragments,and proteins that are transferred from donor cells to recipient cells.Tumor cells release exo-somes to reprogram the factors associated with t...Exosomes are small membrane vesicles containing microRNA,RNA,DNA fragments,and proteins that are transferred from donor cells to recipient cells.Tumor cells release exo-somes to reprogram the factors associated with the tumor microenvironment(TME)causing tu-mor metastasis and immune escape.Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1(PD-L1)that binds with re-ceptor program death protein 1(PD-1)and promote tumor progression by escaping immune response.Currently,some FDA-approved monoclonal antibodies are clinicallyused for cancer treatment by blocking PD-1/PD-L1 interaction.Despite notable treatment outcomes,some pa-tients show poor drug response.Exosomal PD-L1 plays a vital role in lowering the treatment response,showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the ef-fect of cell surface PD-L1.To enhance therapeutic response,inhibition of exosomal PD-L1 is required.Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors.Im-mune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine,nifedipine,lercanidipine,diltiazem,and verapamil were also reported to suppress cellular PD-L1 expression.Therefore,to enhance the PD-1/PD-L1 blockage therapy response,the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consider-ation.In this review,we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.展开更多
The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an impo...The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.展开更多
Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and...Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades.Furthermore,the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy,thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.展开更多
Recent studies have demonstrated that chloroplasts and mitochondria evoke specific Ca2＋ signals in response to biotic and abiotic stresses in a stress-dependent manner. The identification of Ca2＋ transporters and Ca...Recent studies have demonstrated that chloroplasts and mitochondria evoke specific Ca2＋ signals in response to biotic and abiotic stresses in a stress-dependent manner. The identification of Ca2＋ transporters and Ca2＋signaling mol- ecules in chloroplasts and mitochondria implies that they play roles in controlling not only intra-organellar functions, but also extra-organellar processes such as plant immunity and stress responses. It appears that organellar Ca2＋ signaling might be more important to plant cell functions than previously thought. This review briefly summarizes what is known about the molecular basis of Ca2＋ signaling in plant mitochondria and chloroplasts.展开更多
Calcium acts as a second messenger for signaling to a variety of stimuli including MAMPs （Microbe-Associated Molecular Patterns）, such as fig22 and elf18 that are derived from bacterial flagellin and elongation fact...Calcium acts as a second messenger for signaling to a variety of stimuli including MAMPs （Microbe-Associated Molecular Patterns）, such as fig22 and elf18 that are derived from bacterial flagellin and elongation factor Tu, respectively. Here, Arabidopsis thaliana mutants with changed calcium elevation （cce） in response to fig22 treatment were isolated and characterized. Besides novel mutant alleles of the fig22 receptor, FLS2 （Flagellin-Sensitive 2）, and the receptor-associated kinase, BAK1 （Brassinosteroid receptor 1-Associated Kinase 1）, the new cce mutants can be categorized into two main groups--those with a reduced or an enhanced calcium elevation. Moreover, cce mutants from both groups show differ- ential phenotypes to different sets of MAMPs. Thus, these mutants will facilitate the discovery of novel components in early MAMP signaling and bridge the gaps in current knowledge of calcium signaling during plant-microbe interactions. Last but not least, the screening method is optimized for speed （covering 384 plants in 3 or 10 h） and can be adapted to genetically dissect any other stimuli that induce a change in calcium levels.展开更多
P-selectin engagement of P-selectin glycoprotein Iigand-1 （PSGL-1） causes circulating leukocytes to roll on and adhere to the vascular surface, and mediates intracellular calcium flux, a key but unclear event for su...P-selectin engagement of P-selectin glycoprotein Iigand-1 （PSGL-1） causes circulating leukocytes to roll on and adhere to the vascular surface, and mediates intracellular calcium flux, a key but unclear event for subsequent arresting firmly at and migrating into the infection or injured tissue. Using a parallel plate flow chamber technique and intracellular calcium ion detector （Fluo-4 AM）, the intracellular calcium flux of firmly adhered neutrophils on immobilized P-selectin in the absence of chemokines at various wall shear stresses was investigated here in real time by fluorescence microscopy. The results demon- strated that P-selectin engagement of PSGL-1 induced the intracellular calcium flux of firmly adhered neutrophils in flow, increasing P-selectin concentration enhanced cellu- lar calcium signaling, and, force triggered, enhanced and quickened the cytoplasmic calcium bursting of neu- trophils on immobilized P-selectin. This P-selectin-induced calcium signaling should come from intracellular calcium release rather than extracellular calcium influx, and be along the mechano-chemical signal pathway involving the cytoskeleton, moesin and Spleen tyrosine kinase （Syk）. These results provide a novel insight into the mechano-chemical regulation mechanism for P-selectininduced calcium signaling of neutrophils in flow.展开更多
Autosomal dominant polycystic kidney disease （ADPKD） is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimate...Autosomal dominant polycystic kidney disease （ADPKD） is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 （PC1）, a large multi-functional memb-rane receptor protein able to regulate ion channel complexes, whereas polycystin-2 （PC2）, encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum （ER）. In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this feld could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.展开更多
OBJECTIVE:To observe the regulation of electroacupuncture on gene expression at calcium signaling pathways in mice with cerebral ischemia reperfusion.METHODS:Sixty male, inbred Kunming mice were randomly assigned to t...OBJECTIVE:To observe the regulation of electroacupuncture on gene expression at calcium signaling pathways in mice with cerebral ischemia reperfusion.METHODS:Sixty male, inbred Kunming mice were randomly assigned to three groups:repeated cerebral ischemia reperfusion group(RG, n = 24),sham-operated group(SG, n = 12), and electroacupuncture group(EG, n = 24).Mice in RG and EGgroups were modeled by repeated cerebral ischemia reperfusion surgery, and EG mice were treated with electroacupuncture for 30 min after recovery from anesthesia.Changes in gene expression profile of mice hippocampi were analyzed by global expression profile microarray.Genes that were up-regulated or down-regulated greater than 1.5folds were considered to be biologically meaningful.Real-time quantitative polymerase chain reaction(q-PCR) method was used to verify the expression of selected genes based on the algorithm [2^(ΔΔCt)].RESULTS:Compared with SG mice, 242 genes showed different in expressions in RG mice:107down-regulated and 135 up-regulated.Compared with RG mice, 609 genes showed a difference of expression in EG mice:315 down-regulated and 375up-regulated.Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated two pathways:calcium signaling and long-term potentiation in which 11 differentially expressed genes selected.Six of the 11 genes in the calcium signaling pathway were verified after real-time q-PCR testing.CONCLUSION:Electroacupuncture treatment of cerebral ischemia reperfusion appears to regulate Atp2a2, Cacna1 e, Camk2 a, Gnas, Grm1, Rapgef3 genes in the calcium signaling pathway.展开更多
Calcium is important for life. Studies over the last several decades have gradually revealed the critical involvement of calcium, especially its ionic form （Ca2＋）, in every aspect of life forms on earth. Among them...Calcium is important for life. Studies over the last several decades have gradually revealed the critical involvement of calcium, especially its ionic form （Ca2＋）, in every aspect of life forms on earth. Among them, a great deal of work has been done to illustrate how Ca2＋ levels are regulated in the cytoplasm and how many of the cytosolic enzymes and sig- naling molecules respond to the rise and fall of intracellular Ca2＋ concentrations （[Ca2＋]i）. Thanks to the men and wom- en who worked tirelessly for numerous hours in the labora- tory, who made meticulous efforts to invent powerful and innovative tools, and who thought extremely hard to solve the difficult puzzles on signaling pathways, we now know so much about this spectacular cellular functioning process,展开更多
The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal trans...The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal transduction mechanisms.During the late 1980s,we showed that Ca2+-stores can be mobilized by two other messengers unrelated to inositol trisphosphate(IP 3) and identified them as cyclic ADP-ribose(cADPR),a novel cyclic nucleotide from NAD,and nicotinic acid adenine dinucleotide phosphate(NAADP),a linear metabolite of NADP.Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms.Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum,while that of NAADP is the two pore channel in endolysosomes. As cADPR and NAADP are structurally and functionally distinct,it is remarkable that they are synthesized by the same enzyme.They are thus fraternal twin messengers.We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and,through homology,found its mammalian homolog,CD38.Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion,susceptibility to bacterial infection,to social behavior of mice through modulating neuronal oxytocin secretion.We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis.This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components.展开更多
Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Tr...Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Trp and L-Phe),small peptides,anions(e.g.,HCO_(3)^(-)and PO_(4)^(3-)),and pH.CaSR-mediated intracellular Ca^(2+)signaling regulates a diverse set of cellular processes including gene transcription,cell proliferation,differentiation,apoptosis,muscle contraction,and neuronal transmission.Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia,familial hypocalciuric hypercalcemia,and neonatal severe hyperparathyroidism.CaSR also influences calciotropic disorders,such as osteoporosis,and noncalciotropic disorders,such as cancer,Alzheimer's disease,and pulmonary arterial hypertension.This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands,as well as exogenous positive allosteric modulators and negative allosteric modulators.The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum,trafficking,cell surface expression,endocytosis,degradation,and signaling pathways.The roles of these proteins in Ca^(2+)-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.展开更多
Background:The ORAI family of proteins,comprising ORAI1,ORAI2,and ORAI3,plays a crucial role in the regulation of intracellular calcium signaling,which is essential for various cellular functions including proliferati...Background:The ORAI family of proteins,comprising ORAI1,ORAI2,and ORAI3,plays a crucial role in the regulation of intracellular calcium signaling,which is essential for various cellular functions including proliferation,differentiation,and apoptosis.Dysregulation of calcium signaling has been implicated in cancer pathogenesis,influencing tumor progression,metastasis,and resistance to therapy.This study aims to provide a comprehensive analysis of the ORAI family members across a broad spectrum of cancers.Methods:Publicly available datasets from The Cancer Genome Atlas and the Gene Expression Omnibus were utilized.RNA sequencing data,mutation profiles,copy number variation data,and methylation data across different cancer types were analyzed.Differential expression analysis,survival analysis,copy number variation analysis,mutation analysis,methylation analysis,immune cell infiltration analysis using the Cibersort algorithm,and gene set enrichment analysis were conducted using R software.Results:ORAI1 and ORAI3 were significantly upregulated in glioblastoma multiforme,whereas ORAI2 was notably downregulated in kidney chromophobe and pancreatic adenocarcinoma.ORAI2 exhibited higher mutation rates and copy number gains in multiple cancers compared to ORAI1 and ORAI3.The hypermethylation of ORAI2 in head and neck squamous cell carcinoma,esophageal carcinoma,and glioblastoma multiforme negatively correlated with its gene expression.ORAI1 and ORAI3 expression positively correlated with regulatory T cells infiltration,whereas ORAI2 showed a negative correlation with CD8^(+)T cell infiltration.Gene set enrichment analysis revealed that ORAI1 and ORAI2 are associated with immune-related pathways,while ORAI3 is linked to MYC targets and oxidative phosphorylation.Conclusion:Our pan-cancer analysis reveals significant differential expression,genomic alterations,and epigenetic regulation of ORAI family members across various cancers.ORAI1 and ORAI3 appear to promote an immunosuppressive environment,whereas ORAI2 may function as a tumor suppressor in certain contexts.These findings provide a foundation for future research targeting ORAI-mediated pathways in cancer therapy and highlight the therapeutic potential of ORAI proteins.展开更多
As the indispensable second cellular messenger,calcium signaling is involved in the regulation of almost all physiological processes by activating specific target proteins.The importance of calcium ions(Ca^(2+))makes ...As the indispensable second cellular messenger,calcium signaling is involved in the regulation of almost all physiological processes by activating specific target proteins.The importance of calcium ions(Ca^(2+))makes its“Janus nature”strictly regulated by its concentration.Abnormal regulation of calcium signals may cause some diseases;however,artificial regulation of calcium homeostasis in local lesions may also play a therapeutic role.“Calcium overload,”for example,is characterized by excessive enrichment of intracellular Ca^(2+),which irreversibly switches calcium signaling from“positive regulation”to“reverse destruction,”leading to cell death.However,this undesirable death could be defined as“calcicoptosis”to offer a novel approach for cancer treatment.Indeed,Ca^(2+)is involved in various cancer diagnostic and therapeutic events,including calcium overload-induced calcium homeostasis disorder,calcium channels dysregulation,mitochondrial dysfunction,calcium-associated immunoregulation,cell/vascular/tumor calcification,and calcification-mediated CT imaging.In paral-lel,the development of multifunctional calcium-based nanomaterials(e.g.,calcium phosphate,calcium carbonate,calcium peroxide,and hydroxyapatite)is becoming abundantly available.This review will highlight the latest insights of the calcium-based nanomaterials,explain their application,and provide novel perspective.Identifying and characterizing new patterns of calcium-dependent signaling and exploiting the disease element linkage offer additional translational opportunities for cancer theranostics.展开更多
Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest...Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest challenge for medical staff;however,there are currently few effective therapeutic targets for secondary damage.Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system.Homer signaling can exert either positive or negative effects during such insults,depending on the specific subtype of Homer protein.Homer 1b/c couples with other proteins to form postsynaptic densities,which form the basis of synaptic transmission,while Homer 1a expression can be induced by harmful external factors.Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells,mediated or affected by extracellular or intracellular signaling or cytoskeletal processes.This review summarizes the structural features,related signaling pathways,and diverse roles of Homer proteins in physiological and pathological processes.Upregulating Homer 1a or downregulating Homer 1b/c may play a neuroprotective role in secondary brain injuries.Homer also plays an important role in the formation of photoreceptor synapses.These findings confirm the neuroprotective effects of Homer,and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.展开更多
基金supported by the National Science Foundation of China (32171941,31571583)。
文摘Plant calmodulins(CaMs)and calmodulin-like proteins(CMLs)mediate Ca~(2+)signaling in response to abiotic stresses.Manipulation of this signaling in crops could increase stress tolerance.We review methods for detecting Ca~(2+)signals,regulatory roles of Ca Ms and CMLs,binding targets,and Ca~(2+)networks under abiotic stress in organelles.
基金supported by National Key Research and Development Program of China(2022YFD1200300)Jiangsu Key R&D Program(BE2022384)the Collaborative Innovation Center for Modern Crop Production co-sponsored by Province and Ministry(CIC-MCP)(No.10)。
文摘Mitochondrial calcium uniporter(MCU)is a conserved calcium ion(Ca^(2+))transporter in the mitochondrial inner membrane of eukaryotic cells.How MCU proteins regulate Ca^(2+)flow and modulate plant cell development remain largely unclear.Here,we identified the gene GhMCU4 encoding a MCU protein that negatively regulates plant development and fiber elongation in cotton(Gossypium hirsutum).GhMCU4expressed constitutively in various tissues with the higher transcripts in elongating fiber cells.Knockdown of GhMCU4 in cotton significantly elevated the plant height and root length.The calcium signaling pathway was significantly activated and calcium sensor genes,including Ca^(2+)dependent modulator of interactor of constitutively active ROP(GhCMI1),calmodulin like protein(GhCML46),calciumdependent protein kinases(GhCPKs),calcineurin B-like protein(GhCBLs),and CBL-interacting protein kinases(GhCIPKs),were dramatically upregulated in GhMCU4-silenced plants.Metabolic processes were preferentially enriched,and genes related to regulation of transcription were upregulated in GhMCU4-silenced plants.The contents of Ca^(2+)and H_(2)O_(2)were significantly increased in roots and leaves of GhMCU4-silenced plants.Fiber length and Ca^(2+)and H_(2)O_(2)contents in fibers were significantly increased in GhMCU4-silenced plants.This study indicated that GhMCU4 plays a negative role in regulating cell elongation in cotton,thus expanding understanding in the role of MCU proteins in plant growth and development.
基金This study was supported by the National Natural Science Foundation of China(No.81830114 and 82104707)the Natural Science Foundation of Guangdong of China(No.2023A1515011149)+4 种基金Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine(No.202102010014)the Project of Administration of Traditional Chinese Medicine of Guangdong Province of China(No.20221103)the China Postdoctoral Science Foundation(No.2020M683206)Basic and Applied Basic Research Project of Guangzhou Basic Research Plan(No.202201011264)the Fundamental Research Funds for the Central Universities(No.21621001)。
文摘Background:Kai-Xin-San,a classical Chinese medicine prescription,has been widely applied in the clinical therapy for depression,but its pharmacological mechanism remains to be further explored.Based on network pharmacology,molecular docking and animal experiments,the research is performed to exploit pharmacological mechanism of Kai-Xin-San for treating depression.Methods:Obtain chemical components and potential targets of Kai-Xin-San through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,Encyclopedia of Traditional Chinese Medicine and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine databases,and then screen the active ingredients of each herb in accordance with absorption,distribution,metabolism,and excretion.The GenCards,Online Mendelian Inheritance in Man,Therapeutic Target database and DrugBank databases were used to obtain the major targets of depression,and the STRING platform was used to construct the protein-protein interaction network and explore the potential protein functional modules in the network.The targets were subjected to Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis by STRING database and Metascape database.The interaction network of“Kai-Xin-San active components-depression-targets-pathways”was constructed by Cytoscape,and molecular docking verification was performed by Auto Dock tools.Finally,animal experiments were carried out for further verification.The chronic restraint stress depression model was established and mice were randomly divided into 4 groups:control group,chronic restraint stress group,fluoxetine group and Kai-Xin-San group.Behavioral tests were used to evaluate the depressive phenotype of mice.The expression of CaMKII-,synaptophysin,poststroke depression-95,and CACNA1C were all detected using a western blot.Results:Network analysis shows that Kai-Xin-San may mainly regulate calcium signaling pathway to exert antidepressant effects.A majority of the targets and components have good binding activity,according to the molecular docking studies.In the current study,behavioral tests showed that Kai-Xin-San could effectively alleviate depression-like behaviors in mice compared with the chronic restraint stress group,which effect was comparable to fluoxetine.Meanwhile,compared with the chronic restraint stress group,protein levels of CACNA1C,CaMKII-α,synaptophysin and poststroke depression-95 were significantly increased(P<0.05).Conclusion:The research initially identifies the multi-component,multi-target,and multi-path mechanism of Kai-Xin-San in the treatment of depression.Kai-Xin-San may improve synaptic plasticity through calcium signaling pathway to exert antidepressant effects.
基金Supported by grants from the National Natural Science Foundation of China No.30171167,No.30901945the Specialized Research Fund for the Doctoral Program of Higher Education No.20130201130009
文摘Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy. The pathogenesis of pancreatitis is still not well understood. Calcium (Ca<sup>2+</sup>) is a versatile carrier of signals regulating many aspects of cellular activity and plays a central role in controlling digestive enzyme secretion in pancreatic acinar cells. Ca<sup>2+</sup> overload is a key early event and is crucial in the pathogenesis of many diseases. In pancreatic acinar cells, pathological Ca<sup>2+</sup> signaling (stimulated by bile, alcohol metabolites and other causes) is a key contributor to the initiation of cell injury due to prolonged and global Ca<sup>2+</sup> elevation that results in trypsin activation, vacuolization and necrosis, all of which are crucial in the development of pancreatitis. Increased release of Ca<sup>2+</sup> from stores in the intracellular endoplasmic reticulum and/or increased Ca<sup>2+</sup> entry through the plasma membrane are causes of such cell damage. Failed mitochondrial adenosine triphosphate (ATP) production reduces re-uptake and extrusion of Ca<sup>2+</sup> by the sarco/endoplasmic reticulum Ca<sup>2+</sup>-activated ATPase and plasma membrane Ca<sup>2+</sup>-ATPase pumps, which contribute to Ca<sup>2+</sup> overload. Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca<sup>2+</sup> signals in pancreatitis. The lack of available specific treatments is therefore an objective of ongoing research. Research is currently underway to establish the mechanisms and interactions of Ca<sup>2+</sup> signals in the pathogenesis of pancreatitis.
基金supported by the National Natural Science Foundation of China (Grant No. 31071353) the Open Fund of Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization of Huanggang Normal University, China (Grant Nos. 2013000503 and 2011BLKF243)
文摘Calcium ions （Ca2＋） act as an intracellular second messenger and affect nearly all aspects of cellular life. They are functioned by interacting with polar auxin transport, and the negative phototropism of plant roots is caused by the transport of auxin from the irradiated side to the shaded side of the roots. To clarify the role of calcium signaling in the modulation of rice root negative phototropism, as well as the relationship between polar auxin transport and calcium signaling, calcium signaling reagents were used to treat rice seminal roots which were cultivated in hydroculture and unilaterally illuminated at an intensity of 100-200 pmol/（m2.s） for 24 h. Negative phototropism curvature and growth rate of rice roots were both promoted by exogenous CaCI2 lower than 100 pmol/L, but inhibited by calcium channel blockers （verapamil and LaCI3）, calcineurin inhibitor （chlorpromazine, CPZ）, and polar auxin transport inhibitor （N-l-naphthylphthalamic acid, NPA）. Roots stopped growing and negative phototropism disappeared when the concentrations increased to 100 pmol/L verapamil, 12.500 ~Jmol/L LaCI3, 60 pmol/L CPZ, and 6 pmol/L NPA. Moreover, 100 pmol/L CaCI2 could relieve the inhibition of LaCI3, verapamil and NPA. The enhanced negative phototropism curvature was caused by the transportation of more auxin from the irradiated side to the shaded side in the presence of exogenous Ca2＋. Calcium signaling plays a key role as a second messenger in the process of light signal regulation of rice root growth and negative phototropism.
基金supported by the Start-up Foundation for Introduced Talents in Qingdao University of Science and Technology
文摘The potential involvement of calcium in signalling in cyanobacteria has been investigated in recent years. Enough evidences showed that the cyanobacteria were capable of sensing and distinguishing different environmental stimuli, and making responses in ways of Ca^2＋ transients, which were the results of influx or efflux of Ca^2＋ aroused by different environmental stimuli. The calcium signal elicited by nitrogen starvation was crucial to heterocyst differentiation in filamentous cyanobacteria Anabaena species. Identification of a calcium-binding protein （CcbP） from Anabaena sp. PCC 7120 provided further evidence, and the degradation and down-regulation of CcbP accounted for the generation of calcium signal when nitrogen starvation exits. However, the encoding and decoding mechanisms of the calcium signals in cyanobacteria still remain unclear. In order to reveal the exact role of it, a detailed, systematic investigation will be needed, especially for the calcium dynamics at the single cell level.
基金supported by the National Institutes of Health(No.R01 CA266579 to Zhiguo Li)partially supported by the UK CARES Career Development Program(No.P30 ES026529)theAmerican CancerSociety(No.IRG19-140-31).
文摘Exosomes are small membrane vesicles containing microRNA,RNA,DNA fragments,and proteins that are transferred from donor cells to recipient cells.Tumor cells release exo-somes to reprogram the factors associated with the tumor microenvironment(TME)causing tu-mor metastasis and immune escape.Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1(PD-L1)that binds with re-ceptor program death protein 1(PD-1)and promote tumor progression by escaping immune response.Currently,some FDA-approved monoclonal antibodies are clinicallyused for cancer treatment by blocking PD-1/PD-L1 interaction.Despite notable treatment outcomes,some pa-tients show poor drug response.Exosomal PD-L1 plays a vital role in lowering the treatment response,showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the ef-fect of cell surface PD-L1.To enhance therapeutic response,inhibition of exosomal PD-L1 is required.Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors.Im-mune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine,nifedipine,lercanidipine,diltiazem,and verapamil were also reported to suppress cellular PD-L1 expression.Therefore,to enhance the PD-1/PD-L1 blockage therapy response,the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consider-ation.In this review,we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.
基金supported by the National Natural Science Foundation of China,No.82371444(to YZ)the Natural Science Foundation of Hubei Province,No.2022CFB216(to XC)the Key Research Project of Ministry of Science and Technology of China,No.2022ZD021160(to YZ)。
文摘The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.
基金supported by the National Natural Science Foundation of China,Nos.62027812(to HS),81771470(to HS),and 82101608(to YL)Tianjin Postgraduate Research and Innovation Project,No.2020YJSS122(to XD)。
文摘Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades.Furthermore,the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy,thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.
文摘Recent studies have demonstrated that chloroplasts and mitochondria evoke specific Ca2＋ signals in response to biotic and abiotic stresses in a stress-dependent manner. The identification of Ca2＋ transporters and Ca2＋signaling mol- ecules in chloroplasts and mitochondria implies that they play roles in controlling not only intra-organellar functions, but also extra-organellar processes such as plant immunity and stress responses. It appears that organellar Ca2＋ signaling might be more important to plant cell functions than previously thought. This review briefly summarizes what is known about the molecular basis of Ca2＋ signaling in plant mitochondria and chloroplasts.
基金This work was supported by a Deutsche Forschungsgemeinschaft (DFG) grant，financed by the DFG grant，by the Swiss National Science Foundation grant
文摘Calcium acts as a second messenger for signaling to a variety of stimuli including MAMPs （Microbe-Associated Molecular Patterns）, such as fig22 and elf18 that are derived from bacterial flagellin and elongation factor Tu, respectively. Here, Arabidopsis thaliana mutants with changed calcium elevation （cce） in response to fig22 treatment were isolated and characterized. Besides novel mutant alleles of the fig22 receptor, FLS2 （Flagellin-Sensitive 2）, and the receptor-associated kinase, BAK1 （Brassinosteroid receptor 1-Associated Kinase 1）, the new cce mutants can be categorized into two main groups--those with a reduced or an enhanced calcium elevation. Moreover, cce mutants from both groups show differ- ential phenotypes to different sets of MAMPs. Thus, these mutants will facilitate the discovery of novel components in early MAMP signaling and bridge the gaps in current knowledge of calcium signaling during plant-microbe interactions. Last but not least, the screening method is optimized for speed （covering 384 plants in 3 or 10 h） and can be adapted to genetically dissect any other stimuli that induce a change in calcium levels.
基金ACKNOWLEDGEMENTS This work was supported by the National Natural Science Foundation of China [Grant Nos. 11432006 （JW）, 31170887 （JW） and 11272125 （YF）] and by the Fundamental Research Funds for the Central Universities （SCUT） （JW）.
文摘P-selectin engagement of P-selectin glycoprotein Iigand-1 （PSGL-1） causes circulating leukocytes to roll on and adhere to the vascular surface, and mediates intracellular calcium flux, a key but unclear event for subsequent arresting firmly at and migrating into the infection or injured tissue. Using a parallel plate flow chamber technique and intracellular calcium ion detector （Fluo-4 AM）, the intracellular calcium flux of firmly adhered neutrophils on immobilized P-selectin in the absence of chemokines at various wall shear stresses was investigated here in real time by fluorescence microscopy. The results demon- strated that P-selectin engagement of PSGL-1 induced the intracellular calcium flux of firmly adhered neutrophils in flow, increasing P-selectin concentration enhanced cellu- lar calcium signaling, and, force triggered, enhanced and quickened the cytoplasmic calcium bursting of neu- trophils on immobilized P-selectin. This P-selectin-induced calcium signaling should come from intracellular calcium release rather than extracellular calcium influx, and be along the mechano-chemical signal pathway involving the cytoskeleton, moesin and Spleen tyrosine kinase （Syk）. These results provide a novel insight into the mechano-chemical regulation mechanism for P-selectininduced calcium signaling of neutrophils in flow.
基金Supported by University of Ferrara local funds:FAR 2012,2013,2014 and Regione Emilia Romagna grant(Ricerca Regione-Università)2007-2009
文摘Autosomal dominant polycystic kidney disease （ADPKD） is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 （PC1）, a large multi-functional memb-rane receptor protein able to regulate ion channel complexes, whereas polycystin-2 （PC2）, encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum （ER）. In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this feld could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.
基金Supported by the 2013 National Natural Science Foundation of China:The Effect of Electro-acupuncture for Mediating Jnk Mitochondrial Pathway in Bax-gene Knockout Mice With the Cerebral Ischemia Reperfusion(No.81373731)
文摘OBJECTIVE:To observe the regulation of electroacupuncture on gene expression at calcium signaling pathways in mice with cerebral ischemia reperfusion.METHODS:Sixty male, inbred Kunming mice were randomly assigned to three groups:repeated cerebral ischemia reperfusion group(RG, n = 24),sham-operated group(SG, n = 12), and electroacupuncture group(EG, n = 24).Mice in RG and EGgroups were modeled by repeated cerebral ischemia reperfusion surgery, and EG mice were treated with electroacupuncture for 30 min after recovery from anesthesia.Changes in gene expression profile of mice hippocampi were analyzed by global expression profile microarray.Genes that were up-regulated or down-regulated greater than 1.5folds were considered to be biologically meaningful.Real-time quantitative polymerase chain reaction(q-PCR) method was used to verify the expression of selected genes based on the algorithm [2^(ΔΔCt)].RESULTS:Compared with SG mice, 242 genes showed different in expressions in RG mice:107down-regulated and 135 up-regulated.Compared with RG mice, 609 genes showed a difference of expression in EG mice:315 down-regulated and 375up-regulated.Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated two pathways:calcium signaling and long-term potentiation in which 11 differentially expressed genes selected.Six of the 11 genes in the calcium signaling pathway were verified after real-time q-PCR testing.CONCLUSION:Electroacupuncture treatment of cerebral ischemia reperfusion appears to regulate Atp2a2, Cacna1 e, Camk2 a, Gnas, Grm1, Rapgef3 genes in the calcium signaling pathway.
文摘Calcium is important for life. Studies over the last several decades have gradually revealed the critical involvement of calcium, especially its ionic form （Ca2＋）, in every aspect of life forms on earth. Among them, a great deal of work has been done to illustrate how Ca2＋ levels are regulated in the cytoplasm and how many of the cytosolic enzymes and sig- naling molecules respond to the rise and fall of intracellular Ca2＋ concentrations （[Ca2＋]i）. Thanks to the men and wom- en who worked tirelessly for numerous hours in the labora- tory, who made meticulous efforts to invent powerful and innovative tools, and who thought extremely hard to solve the difficult puzzles on signaling pathways, we now know so much about this spectacular cellular functioning process,
基金supported by the Research Grants Council of Hong Kong(Grant Nos.769107,768408, 769309 and 770610)the National Natural Science Foundation of China/the Research Grants Council of Hong Kong(Grant No.N_HKU 722/08)
文摘The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal transduction mechanisms.During the late 1980s,we showed that Ca2+-stores can be mobilized by two other messengers unrelated to inositol trisphosphate(IP 3) and identified them as cyclic ADP-ribose(cADPR),a novel cyclic nucleotide from NAD,and nicotinic acid adenine dinucleotide phosphate(NAADP),a linear metabolite of NADP.Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms.Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum,while that of NAADP is the two pore channel in endolysosomes. As cADPR and NAADP are structurally and functionally distinct,it is remarkable that they are synthesized by the same enzyme.They are thus fraternal twin messengers.We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and,through homology,found its mammalian homolog,CD38.Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion,susceptibility to bacterial infection,to social behavior of mice through modulating neuronal oxytocin secretion.We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis.This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components.
文摘Calcium-sensing receptor(CaSR),a family C G-protein-coupled receptor,plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca^(2+),Mg^(2+),amino acids(e.g.,L-Trp and L-Phe),small peptides,anions(e.g.,HCO_(3)^(-)and PO_(4)^(3-)),and pH.CaSR-mediated intracellular Ca^(2+)signaling regulates a diverse set of cellular processes including gene transcription,cell proliferation,differentiation,apoptosis,muscle contraction,and neuronal transmission.Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia,familial hypocalciuric hypercalcemia,and neonatal severe hyperparathyroidism.CaSR also influences calciotropic disorders,such as osteoporosis,and noncalciotropic disorders,such as cancer,Alzheimer's disease,and pulmonary arterial hypertension.This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands,as well as exogenous positive allosteric modulators and negative allosteric modulators.The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum,trafficking,cell surface expression,endocytosis,degradation,and signaling pathways.The roles of these proteins in Ca^(2+)-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:The ORAI family of proteins,comprising ORAI1,ORAI2,and ORAI3,plays a crucial role in the regulation of intracellular calcium signaling,which is essential for various cellular functions including proliferation,differentiation,and apoptosis.Dysregulation of calcium signaling has been implicated in cancer pathogenesis,influencing tumor progression,metastasis,and resistance to therapy.This study aims to provide a comprehensive analysis of the ORAI family members across a broad spectrum of cancers.Methods:Publicly available datasets from The Cancer Genome Atlas and the Gene Expression Omnibus were utilized.RNA sequencing data,mutation profiles,copy number variation data,and methylation data across different cancer types were analyzed.Differential expression analysis,survival analysis,copy number variation analysis,mutation analysis,methylation analysis,immune cell infiltration analysis using the Cibersort algorithm,and gene set enrichment analysis were conducted using R software.Results:ORAI1 and ORAI3 were significantly upregulated in glioblastoma multiforme,whereas ORAI2 was notably downregulated in kidney chromophobe and pancreatic adenocarcinoma.ORAI2 exhibited higher mutation rates and copy number gains in multiple cancers compared to ORAI1 and ORAI3.The hypermethylation of ORAI2 in head and neck squamous cell carcinoma,esophageal carcinoma,and glioblastoma multiforme negatively correlated with its gene expression.ORAI1 and ORAI3 expression positively correlated with regulatory T cells infiltration,whereas ORAI2 showed a negative correlation with CD8^(+)T cell infiltration.Gene set enrichment analysis revealed that ORAI1 and ORAI2 are associated with immune-related pathways,while ORAI3 is linked to MYC targets and oxidative phosphorylation.Conclusion:Our pan-cancer analysis reveals significant differential expression,genomic alterations,and epigenetic regulation of ORAI family members across various cancers.ORAI1 and ORAI3 appear to promote an immunosuppressive environment,whereas ORAI2 may function as a tumor suppressor in certain contexts.These findings provide a foundation for future research targeting ORAI-mediated pathways in cancer therapy and highlight the therapeutic potential of ORAI proteins.
基金supported by the Major State Basic Research Development Program of China(No.2017YFA0205201)China Postdoctoral Science Foundation Funded Project(2021M702743)the National Natural Science Foundation of China(NSFC,Nos.81925019,32101113,and U1705281).
文摘As the indispensable second cellular messenger,calcium signaling is involved in the regulation of almost all physiological processes by activating specific target proteins.The importance of calcium ions(Ca^(2+))makes its“Janus nature”strictly regulated by its concentration.Abnormal regulation of calcium signals may cause some diseases;however,artificial regulation of calcium homeostasis in local lesions may also play a therapeutic role.“Calcium overload,”for example,is characterized by excessive enrichment of intracellular Ca^(2+),which irreversibly switches calcium signaling from“positive regulation”to“reverse destruction,”leading to cell death.However,this undesirable death could be defined as“calcicoptosis”to offer a novel approach for cancer treatment.Indeed,Ca^(2+)is involved in various cancer diagnostic and therapeutic events,including calcium overload-induced calcium homeostasis disorder,calcium channels dysregulation,mitochondrial dysfunction,calcium-associated immunoregulation,cell/vascular/tumor calcification,and calcification-mediated CT imaging.In paral-lel,the development of multifunctional calcium-based nanomaterials(e.g.,calcium phosphate,calcium carbonate,calcium peroxide,and hydroxyapatite)is becoming abundantly available.This review will highlight the latest insights of the calcium-based nanomaterials,explain their application,and provide novel perspective.Identifying and characterizing new patterns of calcium-dependent signaling and exploiting the disease element linkage offer additional translational opportunities for cancer theranostics.
基金supported by the National Natural Science Foundation of China,Nos.81600738(to FF),81771239(to ZF),81801300(to NS)。
文摘Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest challenge for medical staff;however,there are currently few effective therapeutic targets for secondary damage.Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system.Homer signaling can exert either positive or negative effects during such insults,depending on the specific subtype of Homer protein.Homer 1b/c couples with other proteins to form postsynaptic densities,which form the basis of synaptic transmission,while Homer 1a expression can be induced by harmful external factors.Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells,mediated or affected by extracellular or intracellular signaling or cytoskeletal processes.This review summarizes the structural features,related signaling pathways,and diverse roles of Homer proteins in physiological and pathological processes.Upregulating Homer 1a or downregulating Homer 1b/c may play a neuroprotective role in secondary brain injuries.Homer also plays an important role in the formation of photoreceptor synapses.These findings confirm the neuroprotective effects of Homer,and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.
