Calmodulins and calmodulin-like proteins-mediated plant organellar calcium signaling networks under abiotic stress

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.

Regulation of specific abnormal calcium signals in the hippocampal CA1 and primary cortex M1 alleviates the progression of temporal lobe epilepsy

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.

Suppressing a mitochondrial calcium uniporter activates the calcium signaling pathway and promotes cell elongation in cotton

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.

Research process of the calcium signaling in cyanobacteria

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.

Calcium signaling of pancreatic acinar cells in the pathogenesis of pancreatitis

Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy. The pathogenesis of pancreatitis is still not well understood. Calcium (Ca2+) 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. Ca2+ overload is a key early event and is crucial in the pathogenesis of many diseases. In pancreatic acinar cells, pathological Ca2+ signaling (stimulated by bile, alcohol metabolites and other causes) is a key contributor to the initiation of cell injury due to prolonged and global Ca2+ elevation that results in trypsin activation, vacuolization and necrosis, all of which are crucial in the development of pancreatitis. Increased release of Ca2+ from stores in the intracellular endoplasmic reticulum and/or increased Ca2+ entry through the plasma membrane are causes of such cell damage. Failed mitochondrial adenosine triphosphate (ATP) production reduces re-uptake and extrusion of Ca2+ by the sarco/endoplasmic reticulum Ca2+-activated ATPase and plasma membrane Ca2+-ATPase pumps, which contribute to Ca2+ overload. Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca2+ 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 Ca2+ signals in the pathogenesis of pancreatitis.

Calcium Signaling is Involved in Negative Phototropism of Rice Seminal Roots

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.

Kai-Xin-San regulates synaptic plasticity through calcium signaling to alleviate symptoms of depression-like behavioral disorders in mice

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.

Multilevel complexity of calcium signaling:Modeling angiogenesis

Intracellular calcium signaling is a universal,evolutionary conserved and versatile regulator of cell biochemistry.The complexity of calcium signaling and related cell machinery can be investigated by the use of experimental strategies,as well as by computational approaches.Vascular endothelium is a fascinating model to study the specific properties and roles of calcium signals at multiple biological levels.During the past 20 years,live cell imaging,patch clamp and other techniques have allowed us to detect and interfere with calcium signaling in endothelial cells(ECs),providing a huge amount of information on the regulation of vascularization(angiogenesis) in normal and tumoral tissues.These data range from the spatiotemporal dynamics of calcium within different cell microcompartments to those in entire multicellular and organized EC networks.Beside experimental strategies,in silico endothelial models,specifically designed for simulating calcium signaling,are contributing to our knowledge of vascular physiol-ogy and pathology.They help to investigate and predict the quantitative features of proangiogenic events moving through subcellular,cellular and supracellular levels.This review focuses on some recent developments of computational approaches for proangiogenic endothelial calcium signaling.In particular,we discuss the creation of hybrid simulation environments,which combine and integrate discrete Cellular Potts Models.They are able to capture the phenomenological mechanisms of cell morphological reorganization,migration,and intercellular adhesion,with single-cell spatiotemporal models,based on reaction-diffusion equations that describe the agonist-induced intracellular calcium events.

Emanuel Strehler’s work on calcium pumps and calcium signaling

Cells are equipped with mechanisms to control tightly the influx, efflux and resting level of free calcium (Ca 2+ ). Inappropriate Ca 2+ signaling and abnormal Ca 2+ levels are involved in many clinical disorders including heart disease, Alzheimer's disease and stroke. Ca 2+ also plays a major role in cell growth, differentiation and motility; disturbances in these processes underlie cell transformation and the progression of cancer. Accordingly, research in the Strehler laboratory is focused on a better understanding of the molecular "toolkit" needed to ensure proper Ca 2+ homeostasis in the cell, as well as on the mechanisms of localized Ca 2+ signaling. A longterm focus has been on the plasma membrane calcium pumps (PMCAs), which are linked to multiple disorders including hearing loss, neurodegeneration, and heart disease. Our work over the past 20 years or more has revealed a surprising complexity of PMCA isoforms with different functional characteristics, regulation, and cellular localization. Emerging evidence shows how specific PMCAs contribute not only to setting basal intracellular Ca 2+ levels, but also to local Ca 2+ signaling and vectorial Ca 2+ transport. A second major research arearevolves around the calcium sensor protein calmodulin and an enigmatic calmodulin-like protein (CALML3) that is linked to epithelial differentiation. One of the cellular targets of CALML3 is the unconventional motor protein myosin-10, which raises new questions about the role of CALML3 and myosin-10 in cell adhesion and migration in normal cell differentiation and cancer.

The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy

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.

Glucocorticoid receptor signaling in the brain and its involvement in cognitive function

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.

Calcium Signaling in Plant Endosymbiotic Organelles： Mechanism and Role in Physiology

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.

Defense-Related Calcium Signaling Mutants Uncovered via a Quantitative High-Throughput Screen in Arabidopsis thaliana

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.

A High-Throughput Method for Screening Arabidopsis Mutants with Disordered Abiotic Stress-Induced Calcium Signal

It is established that different stresses cause signal-specific changes in cellular Ca2 ~ level, which function as messengers in modulating diverse physiological processes. These calcium signals are important for stress adaptation. Though numbers of downstream components of calcium signal cascades have been identified, upstream events in calcium signal remain elusive, specifically components required l＇~~r calcium signal generation due to the lack of high-throughput genetic assay. Here, we report the development of an easy and efficient method in a forward genetic screen for Ca2＋ signals-deficient mutants in Arahidopsis thaliana. Using this method, 121 mutants with disordered NaCI- and H=O2-induced Ca2＋ signals are isolated.

Force-dependent calcium signaling and its pathway of human neutrophils on P-selectin in flow

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.

Role of calcium in polycystic kidney disease:From signaling to pathology

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.

Effect of electroacupuncture on gene expression in calcium signaling pathway in hippocampal cells in mice with cerebral ischemia reperfusion

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.

The hills and valleys of calcium signaling

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,

Cyclic ADP-ribose and NAADP:fraternal twin messengers for calcium signaling

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.

A model of calcium signaling and degranulation dynamics induced by laser irradiation in mast cells

Recent experiments show that calcium signaling and degranulation dynamics induced by low power laser irradiation in mast cells must rely on extracellular Ca2+ influx. An analytical expression of Ca2+ flux through TRPV4 cation channel in response to interaction of laser photon energy and extracellular Ca2+ is deduced, and a model characterizing dynamics of calcium signaling and degranulation activated by laser irradiation in mast cells is established. The model indicates that the characteristics of calcium signaling and degranulation dynamics are determined by interaction between laser photon energy and Ca2+ influx. Extracellular Ca2+ concentration is so high that even small photon energy can activate mast cells, thus avoiding the possible injury caused by laser irradiation with shorter wavelengths. The model predicts that there exists a narrow parameter domain of photon energy and extracellular Ca2+ concen-tration of which results in cytosolic Ca2+ limit cycle oscillations, and shows that PKC activity is in direct proportion to the frequency of Ca2+ oscillations. With the model it is found that sustained and stable maximum plateau of cytosolic Ca2+ concentration can get optimal degranulation rate. Furthermore, the idea of introducing the realistic physical energy into model is applicable to modeling other physical signal transduction systems.