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1.
Background
In recent years, as our understanding of the various roles played by Ca2 + signaling in development and differentiation has expanded, the challenge of imaging Ca2 + dynamics within living cells, tissues, and whole animal systems has been extended to include specific signaling activity in organelles and non-membrane bound sub-cellular domains.Scope of review
In this review we outline how recent advances in genetics and molecular biology have contributed to improving and developing current bioluminescence-based Ca2 + imaging techniques. Reporters can now be targeted to specific cell types, or indeed organelles or domains within a particular cell.Major conclusions
These advances have contributed to our current understanding of the specificity and heterogeneity of developmental Ca2 + signaling. The improvement in the spatial resolution that results from specifically targeting a Ca2 + reporter has helped to reveal how a ubiquitous signaling messenger like Ca2 + can regulate coincidental but different signaling events within an individual cell; a Ca2 + signaling paradox that until now has been hard to explain.General significance
Techniques used to target specific reporters via genetic means will have applications beyond those of the Ca2 + signaling field, and these will, therefore, make a significant contribution in extending our understanding of the signaling networks that regulate animal development. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signalling. 相似文献2.
Karin C. Larsson Peter KjällAgneta Richter-Dahlfors 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
A major challenge when creating interfaces for the nervous system is to translate between the signal carriers of the nervous system (ions and neurotransmitters) and those of conventional electronics (electrons).Scope of review
Organic conjugated polymers represent a unique class of materials that utilizes both electrons and ions as charge carriers. Based on these materials, we have established a series of novel communication interfaces between electronic components and biological systems. The organic electronic ion pump (OEIP) presented in this review is made of the polymer–polyelectrolyte system poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). The OEIP translates electronic signals into electrophoretic migration of ions and neurotransmitters.Major conclusions
We demonstrate how spatio-temporally controlled delivery of ions and neurotransmitters can be used to modulate intracellular Ca2 + signaling in neuronal cells in the absence of convective disturbances. The electronic control of delivery enables strict control of dynamic parameters, such as amplitude and frequency of Ca2 + responses, and can be used to generate temporal patterns mimicking naturally occurring Ca2 + oscillations. To enable further control of the ionic signals we developed the electrophoretic chemical transistor, an analog of the traditional transistor used to amplify and/or switch electronic signals. Finally, we demonstrate the use of the OEIP in a new “machine-to-brain” interface by modulating brainstem responses in vivo.General significance
This review highlights the potential of communication interfaces based on conjugated polymers in generating complex, high-resolution, signal patterns to control cell physiology. We foresee widespread applications for these devices in biomedical research and in future medical devices within multiple therapeutic areas. This article is part of a Special Issue entitled Organic Bioelectronics—Novel Applications in Biomedicine. 相似文献3.
Bicheng Yang Xiaolu Duan Wenzheng Wu Weidong JiWenqi Wu Wen ZhongZhijian Zhao Shujue LiYang Liu Guohua Zeng 《Life sciences》2014
Aim
Promoter-targeted small activating RNAs (saRNAs) have been shown to be able to induce target gene expression, a mechanism known as RNA activation (RNAa). The present study tested whether saRNA can induce the overexpression of TRPV5 in human cells derived from the kidney and subsequently manipulate cell calcium uptake.Main methods
Three saRNAs complementary to the TRPV5 promoter were synthesized and transfected into cells. TRPV5 expression at the RNA and protein levels was analyzed by quantitative real-time PCR and Western blotting respectively. For functional study, transcellular Ca2 + transportation was tested by fura-2 analysis. Dihydrotestosterone (DHT), a suppressor of cellular calcium transportation, was administered to challenge the activating effect of selected saRNA.Key findings
One of these synthesized saRNAs, ds-2939, significantly induced the expression of TRPV5 at both mRNA and protein levels. Fura-2 analysis revealed that the intracellular Ca2 + concentration was elevated by ds-2939. DHT treatment reduced transmembrane Ca2 + transport, which was partially antagonized by ds-2939.Significance
Our results suggest that a saRNA targeting TRPV5 promoter can be utilized to manipulate the transmembrane Ca2 + transport by upregulating the expression of TRPV5 and may serve as an alternative for the treatment of Ca2 + balance-related diseases. 相似文献4.
Aims
We have previously demonstrated that propyl gallate has a Ca2 + sensitizing effect on the force generation in membrane-permeabilized (skinned) cardiac muscle fibers. However, in vivo beneficial effects of propyl gallate as a novel Ca2 + sensitizer remain uncertain. In the present study, we aim to explore in vivo effects of propyl gallate.Main methods
We compared effects of propyl gallate on ex vivo intact cardiac muscle fibers and in vivo hearts in healthy mice with those of pimobendan, a clinically used Ca2 + sensitizer. The therapeutic effect of propyl gallate was investigated using a mouse model of dilated cardiomyopathy (DCM) with reduced myofilament Ca2 + sensitivity due to a deletion mutation ΔK210 in cardiac troponin T.Key findings
Propyl gallate, as well as pimobendan, showed a positive inotropic effect. Propyl gallate slightly increased the blood pressure without changing the heart rate in healthy mice, whereas pimobendan decreased the blood pressure probably through vasodilation via inhibition of phosphodiesterase and increased the heart rate. Propyl gallate prevented cardiac remodeling and systolic dysfunction and significantly improved the life-expectancy of knock-in mouse model of DCM with reduced myofilament Ca2 + sensitivity due to a mutation in cardiac troponin T. On the other hand, gallate, a similarly strong antioxidant polyphenol lacking Ca2 + sensitizing action, had no beneficial effects on the DCM mice.Significance
These results suggest that propyl gallate might be useful for the treatment of inherited DCM caused by a reduction in the myofilament Ca2 + sensitivity. 相似文献5.
Thanutchaporn Kumrungsee Tomomi SaikiSayaka Akiyama Kentaro NakashimaMitsuru Tanaka Yutaro KobayashiToshiro Matsui 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Tryptophan-histidine (Trp-His) was found to suppress the activity of the Ca2 +/calmodulin (CaM)-dependent protein kinases II (CaMKII), which requires the Ca2 +-CaM complex for an initial activation. In this study, we attempted to clarify whether Trp-His inhibits Ca2 +-CaM complex formation, a CaMKII activator.Methods
The ability of Trp-His and other peptides to inhibit Ca2 +-CaM complex formation was investigated by a Ca2 +-encapsulation fluorescence assay. The peptide-CaM interactions were illustrated by molecular dynamic simulation.Results
We showed that Trp-His inhibited Ca2 +-CaM complex formation with a 1:1 binding stoichiometry of the peptide to CaM, considering that Trp-His reduced Hill coefficient of Ca2 +-CaM binding from 2.81 to 1.92. His-Trp also showed inhibitory activity, whereas Trp + His, 3-methyl His-Trp, and Phe-His did not show significant inhibitory activity, suggesting that the inhibitory activity was due to a peptide skeleton (irrespective of the sequence), a basic amino acid, a His residue, the N hydrogen atom of its imidazole ring, and Trp residue. In silico studies suggested the possibility that Trp-His and His-Trp interacted with the Ca2 +-binding site of CaM by forming hydrogen bonds with key Ca2 +-binding residues of CaM, with a binding free energy of − 49.1 and − 68.0 kJ/mol, respectively.Conclusions
This is the first study demonstrating that the vasoactive dipeptide Trp-His possesses inhibitory activity against Ca2 +-CaM complex formation, which may elucidate how Trp-His inhibited CaMKII in a previous study.General significance
The results provide a basic idea that could lead to the development of small peptides binding with high affinity to CaM and inhibiting Ca2 +-CaM complex formation in the future. 相似文献6.
Gen-ichiro Arimura Massimo E. Maffei 《Biochemical and biophysical research communications》2010,400(4):455-460
Plant Ca2+ signals are involved in a sizable array of intracellular signaling pathways after pest invasion. Upon herbivore feeding there is a dramatic Ca2+ influx, followed by the activation of Ca2+-dependent signal transduction pathways that include interacting downstream networks of kinases for defense responses. Notably, Ca2+-binding sensory proteins such as Ca2+-dependent protein kinases (CPKs) have recently been documented to mediate the signaling following Ca2+ influx after herbivory, in phytohormone-independent manners. Here, we review the sequence of signal transductions triggered by herbivory-evoked Ca2+ signaling leading to CPK actions for defense responses, and discuss in a comparative way the involvement of CPKs in the signal transduction of a variety of other biotic and abiotic stresses. 相似文献
7.
Theo J. M. Schoenmakers Peter H. M. Klaren Gert Flik Robert A. C. Lock Peter K. T. Pang Sjoerd E. Wendelaar Bonga 《The Journal of membrane biology》1992,127(3):161-172
Summary The inhibition of Ca2–-ATPase, (Na++K+)-ATPase and Na+/Ca2+ exchange by Cd2+ was studied in fish intestinal basolateral plasma membrane preparations. ATP driven 45Ca2+ uptake into inside-out membrane vesicles displayed a K
m
for Ca2+ of 88±17 nm, and was extremely sensitive to Cd2+ with an IC50 of 8.2±3.0 pM Cd2+, indicating an inhibition via the Ca2+ site. (Na++K+)-ATPase activity was half-maximally inhibited by micromolar amounts of Cd2+, displaying an IC50 of 2.6±0.6 m Cd2+. Cd2+ ions apparently compete for the Mg2+ site of the (Na– +K+)-ATPase. The Na+/Ca2+ exchanger was inhibited by Cd2+ with an IC50 of 73±11 nm. Cd2+ is a competitive inhibitor of the exchanger via an interaction with the Ca2+ site (K
i
= 11 nm). Bepridil, a Na+ site specific inhibitor of Na+/Ca2+ exchange, induced an additional inhibition, but did not change the K
i
of Cd2+. Also, Cd2+ is exchanged against Ca2+, albeit to a lesser extent than Ca2+. The exchanger is only partly blocked by the binding of Cd2+. In vivo cadmium that has entered the enterocyte may be shuttled across the basolateral plasma membrane by the Na+/Ca2+ exchanger. We conclude that intracellular Cd2+ ions will inhibit plasma membrane proteins predominantly via a specific interaction with divalent metal ion sites.We would like to thank Dr. D. Fackre (University of Alberta, Canada) for stimulating discussions and Mr. F.A.T. Spanings (University of Nijmegen, The Netherlands) for excellent fish husbandry. The fura-2 measurements of intracellular Ca2+ concentrations in tilapia enterocytes were carried out in the Department of Physiology, School of Medicine, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Th.J.M. Schoenmakers and G. Flik were supported by travel grants from the Foundation for Fundamental Biological Research (BION) and the Netherlands Organization for Scientific Research (NWO). 相似文献
8.
In the present paper we studied the involvement of the phosphatidylinositol-specific PLC (PI-PLC)/protein kinase C (PKC) pathway in (Na+ + K+)ATPase stimulation by heme in Leishmania amazonensis promastigotes. Heme stimulated the PKC-like activity with a concentration of 50 nM. Interestingly, the maximal stimulation of the PKC-like activity promoted by phorbol ester was of the same magnitude promoted by heme. However, the stimulatory effect of heme is completely abolished by ET-18-OCH3 and U73122, specific inhibitors of PI-PLC. (Na+ + K+)ATPase activity is increased in the presence of increased concentrations of heme, being maximally affected at 50 nM. This effect was completely reversed by 10 nM calphostin C, an inhibitor of PKC. Thus, the effect of 50 nM heme on (Na+ + K+)ATPase activity is completely abolished by ET-18-OCH3 and U73122. Taken together, these results demonstrate that the heme receptor mediates the stimulatory effect of heme on the (Na+ + K+)ATPase activity through a PI-PLC/PKC signaling pathway. 相似文献
9.
CaMKIIγ, the predominant CaMKII isoform in mouse eggs, controls egg activation by regulating cell cycle resumption. In this study we further characterize the involvement and specificity of CaMKIIγ in mouse egg activation. Using exogenous expression of different cRNAs in Camk2g−/− eggs, we show that the other multifunctional CaM kinases, CaMKI, and CaMKIV, are not capable of substituting CaMKIIγ to initiate cell cycle resumption in response to a rise in intracellular Ca2+. Exogenous expression of Camk2g or Camk2d results in activation of nearly 80% of Camk2g−/− MII eggs after stimulation with SrCl2, which does not differ from the incidence of activation of wild-type eggs expressing exogenous Egfp. In contrast, none of the Camk2g−/− MII eggs expressing Camk1 or Camk4 activate in response to SrCl2 treatment. Expression of a constitutively active form of Camk4 (ca-Camk4), but not Camk1, triggers egg activation. EMI2, an APC/C repressor, is a key component in regulating egg activation downstream of CaMKII in both Xenopus laevis and mouse. We show that exogenous expression of either Camk2g, Camk2d, or ca-Camk4, but not Camk1, Camk4, or a catalytically inactive mutant form of CaMKIIγ (kinase-dead) in Camk2g−/− mouse eggs leads to almost complete degradation (~90%) of exogenously expressed EMI2 followed by cell cycle resumption. Thus, degradation of EMI2 following its phosphorylation specifically by CaMKII is mechanistically linked to and promotes cell cycle resumption in MII eggs. 相似文献
10.
Depletion of intracellular Ca2 + stores in mammalian cells results in Ca2 + entry across the plasma membrane mediated primarily by Ca2 + release-activated Ca2 + (CRAC) channels. Ca2 + influx through these channels is required for the maintenance of homeostasis and Ca2 + signaling in most cell types. One of the main features of native CRAC channels is fast Ca2 +-dependent inactivation (FCDI), where Ca2 + entering through the channel binds to a site near its intracellular mouth and causes a conformational change, closing the channel and limiting further Ca2 + entry. Early studies suggested that FCDI of CRAC channels was mediated by calmodulin. However, since the discovery of STIM1 and Orai1 proteins as the basic molecular components of the CRAC channel, it has become apparent that FCDI is a more complex phenomenon. Data obtained using heterologous overexpression of STIM1 and Orai1 suggest that, in addition to calmodulin, several cytoplasmic domains of STIM1 and Orai1 and the selectivity filter within the channel pore are required for FCDI. The stoichiometry of STIM1 binding to Orai1 also has emerged as an important determinant of FCDI. Consequently, STIM1 protein expression levels have the potential to be an endogenous regulator of CRAC channel Ca2 + influx. This review discusses the current understanding of the molecular mechanisms governing the FCDI of CRAC channels, including an evaluation of further experiments that may delineate whether STIM1 and/or Orai1 protein expression is endogenously regulated to modulate CRAC channel function, or may be dysregulated in some pathophysiological states. 相似文献
11.
Finger millet (Eleusine coracana) variably accumulates calcium in different tissues, due to differential expression of genes involved in uptake, translocation and accumulation of calcium. Ca2 +/H+ antiporter (CAX1), two pore channel (TPC1), CaM-stimulated type IIB Ca2 + ATPase and two CaM dependent protein kinase (CaMK1 and 2) homologs were studied in finger millet. Two genotypes GP-45 and GP-1 (high and low calcium accumulating, respectively) were used to understand the role of these genes in differential calcium accumulation. For most of the genes higher expression was found in the high calcium accumulating genotype. CAX1 was strongly expressed in the late stages of spike development and could be responsible for accumulating high concentrations of calcium in seeds. TPC1 and Ca2 + ATPase homologs recorded strong expression in the root, stem and developing spike and signify their role in calcium uptake and translocation, respectively. Calmodulin showed strong expression and a similar expression pattern to the type IIB ATPase in the developing spike only and indicating developing spike or even seed specific isoform of CaM affecting the activity of downstream target of calcium transportation. Interestingly, CaMK1 and CaMK2 had expression patterns similar to ATPase and TPC1 in various tissues raising a possibility of their respective regulation via CaM kinase. Expression pattern of 14-3-3 gene was observed to be similar to CAX1 gene in leaf and developing spike inferring a surprising possibility of CAX1 regulation through 14-3-3 protein. Our results provide a molecular insight for explaining the mechanism of calcium accumulation in finger millet. 相似文献
12.
The present study aimed to clarify the existence of a Na+/Ca2+ antiport device in kidney tubular epithelial cells discussed in the literature to represent the predominant mechanistic device for Ca2+ reabsorption in the kidney. (1) Inside-out oriented plasma membrane vesicles from tubular epithelial cells of guinea-pig kidney showed an ATP-driven Ca2+ transport machinery similar to that known to reside in the plasma membrane of numerous cell types. It was not affected by digitalis compounds which otherwise are well-documented inhibitors of Ca2+ reabsorption. (2) The vesicle preparation contained high, digitalis-sensitive (Na++K+-ATPase activities indicating its origin from the basolateral portion of plasma membrane. (3) The operation of Na+/Ca2+ antiport device was excluded by the findings that steep Ca2+ gradients formed by ATP-dependent Ca2+ accumulation in the vesicles were not discharged by extravesicular Na+, and did not drive 45Ca2+ uptake into the vesicles via a Ca2+-45Ca2+ exchange. (4) The ATP-dependent Ca2+ uptake into the vesicles became increasingly depressed with time by extravesicular Na+. This was not due to an impairment of the Ca2+ pump itself, but caused by Na+/Ca2+ competition for binding sites on the intravesicular membrane surface shown to be important for high Ca2+ accumulation in the vesicles. (5) Earlier observations on Na+-induced release of Ca2+ from vesicles pre-equilibrated with Ca2+, seemingly favoring the existence of a Na+/Ca2+ antiporter in the basolateral plasma membrane, were likewise explained by the occurrence of Na+/Ca2+ competition for binding sites. The weight of our findings disfavors the transcellular pathway of Ca2+ reabsorption through tubule epithelium essentially depending on the operation of a Na+/Ca2+ antiport device. 相似文献
13.
Zenon Grabarek 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2011,1813(5):913-921
The Ca2+-binding helix-loop-helix structural motif called “EF-hand” is a common building block of a large family of proteins that function as intracellular Ca2+-receptors. These proteins respond specifically to micromolar concentrations of Ca2+ in the presence of ~1000-fold excess of the chemically similar divalent cation Mg2+. The intracellular free Mg2+ concentration is tightly controlled in a narrow range of 0.5-1.0 mM, which at the resting Ca2+ levels is sufficient to fully or partially saturate the Ca2+-binding sites of many EF-hand proteins. Thus, to convey Ca2+ signals, EF-hand proteins must respond differently to Ca2+ than to Mg2+. In this review the structural aspects of Mg2+ binding to EF-hand proteins are considered and interpreted in light of the recently proposed two-step Ca2+-binding mechanism (Grabarek, Z., J. Mol. Biol., 2005, 346, 1351). It is proposed that, due to stereochemical constraints imposed by the two-EF-hand domain structure, the smaller Mg2+ ion cannot engage the ligands of an EF-hand in the same way as Ca2+ and defaults to stabilizing the apo-like conformation of the EF-hand. It is proposed that Mg2+ plays an active role in the Ca2+-dependent regulation of cellular processes by stabilizing the “off state” of some EF-hand proteins, thereby facilitating switching off their respective target enzymes at the resting Ca2+ levels. Therefore, some pathological conditions attributed to Mg2+ deficiency might be related to excessive activation of underlying Ca2+-regulated cellular processes. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. 相似文献
14.
K. R. Robinson 《Planta》1977,136(2):153-158
The effect of external calcium and sodium ion concentrations on the calcium fluxes on the Pelvetia fastigiata De Toni egg was measured. Decreasing external [Ca2+] greatly increased the permeability of the eggs to Ca2+; at 1 mM external Ca2+ this permeability was 60 times as great as it was at the normal [Ca2+] of 10 mM. Lowering the external [Na+] also increased Ca2+ influx; at 2 mM Na+, the Ca2+ influx was 2–3 times as great as it was at the normal [Na+] if choline was used as a Na+ substitute. Lithium was less effective as a Na+ substitute in increasing Ca2+ influx. The extra Ca2+ influx in low [Na+] seemed to be dependent on internal [Na+]. The Ca2+ efflux increased transiently and then declined in low Na+ media. 相似文献
15.
Calcium signaling by cyclic ADP-ribose and NAADP 总被引:4,自引:0,他引:4
Hon Cheung Lee 《Cell biochemistry and biophysics》1998,28(1):1-17
Ca2+ mobilization as a signaling mechanism has been placed on center stage with the discovery of the first Ca2+ messenger, inositol trisphosphate (IP3). This article focuses on two new Ca2+ release activators, which mobilize internal Ca2+ stores via mechanisms totally independent of IP3. They are cyclic ADP-ribose (cADPR) and nicotinic acid dinucleotide phosphate (NAADP), metabolites derived respectively from
NAD and NADP. Major advances in the past decade in the understanding of these two novel signaling mechanisms are chronologically
summarized. 相似文献
16.
Calcium signaling system in plants 总被引:4,自引:0,他引:4
S. S. Medvedev 《Russian Journal of Plant Physiology》2005,52(2):249-270
17.
Oxygen free radicals and calcium homeostasis in the heart 总被引:10,自引:0,他引:10
Masanori Kaneko Yuji Matsumoto Hideharu Hayashi Akira Kobayashi Noboru Yamazaki 《Molecular and cellular biochemistry》1994,135(1):99-108
Many experiments have been done to clarify the effects of oxygen free radicals on Ca2+ homeostasis in the hearts. A burst of oxygen free radicals occurs immediately after reperfusion, but we have to be reminded that the exact levels of oxygen free radicals in the hearts are yet unknown in both physiological and pathophysiological conditions. Therefore, we should give careful consideration to this point when we perform the experiments and analyze the results. It is, however, evident that Ca2+ overload occurs when the hearts are exposed to an excess amount of oxygen free radicals. Though ATP-independent Ca2+ binding is increased, Ca2+ influx through Ca2+ channel does not increase in the presence of oxygen free radicals. Another possible pathway through which Ca2+ can enter the myocytes is Na+?Ca2+ exchanger. Although, the activities of Na+?K+ ATPase and Na+?H+ exchange are inhibited by oxygen free radicals, it is not known whether intracellular Na+ level increases under oxidative stress or not. The question has to be solved for the understanding of the importance of Na+?Ca2+ exchange in Ca2+ influx process from extracellular space. Another question is ‘which way does Na+?Ca2+ exchange work under oxidative stress? Net influx or efflux of Ca2+?’ Membrane permeability for Ca2+ may be maintained in a relatively early phase of free radical injury. Since sarcolemmal Ca2+-pump ATPase activity is depressed by oxygen free radicals, Ca2+ extrusion from cytosol to extracellular space is considered to be reduced. It has also been shown that oxygen free radicals promote Ca2+ release from sarcoplasmic reticulum and inhibit Ca2+ sequestration to sarcoplasmic reticulum. Thus, these changes in Ca2+ handling systems could cause the Ca2+ overload due to oxygen free radicals. 相似文献
18.
Lipid rafts/caveolae as microdomains of calcium signaling 总被引:1,自引:1,他引:0
Ca2+ is a major signaling molecule in both excitable and non-excitable cells, where it serves critical functions ranging from cell growth to differentiation to cell death. The physiological functions of these cells are tightly regulated in response to changes in cytosolic Ca2+ that is achieved by the activation of several plasma membrane (PM) Ca2+ channels as well as release of Ca2+ from the internal stores. One such channel is referred to as store-operated Ca2+ channel that is activated by the release of endoplasmic reticulum (ER) Ca2+ which initiates store-operated Ca2+ entry (SOCE). Recent advances in the field suggest that some members of TRPCs and Orai channels function as SOCE channels. However, the molecular mechanisms that regulate channel activity and the exact nature of where these channels are assembled and regulated remain elusive. Research from several laboratories has demonstrated that key proteins involved in Ca2+ signaling are localized in discrete PM lipid rafts/caveolar microdomains. Lipid rafts are cholesterol and sphingolipid-enriched microdomains that function as unique signal transduction platforms. In addition lipid rafts are dynamic in nature which tends to scaffold certain signaling molecules while excluding others. By such spatial segregation, lipid rafts not only provide a favorable environment for intra-molecular cross-talk but also aid to expedite the signal relay. Importantly, Ca2+ signaling is shown to initiate from these lipid raft microdomains. Clustering of Ca2+ channels and their regulators in such microdomains can provide an exquisite spatiotemporal regulation of Ca2+-mediated cellular function. Thus in this review we discuss PM lipid rafts and caveolae as Ca2+-signaling microdomains and highlight their importance in organizing and regulating SOCE channels. 相似文献
19.
Persistent tumour necrosis factor alpha (TNF-alpha) exposure uncouples proximal T-cell receptor (TCR)-signalling events. Here, we demonstrate that chronic TNF-alpha exposure also attenuates signalling distal to the TCR, by specifically inhibiting Ca2+ influx evoked by thapsigargin in CD4+ T-cells. Mitogen-induced Ca2+ responses were impaired in a dose dependent manner, and TCR-induced Ca2+ responses were also significantly reduced. The impairment of Ca2+ influx strongly correlated with poor function as proliferative responses to both mitogen and anti-CD3/CD28 stimulation were suppressed. Our findings show that persistent TNF-alpha exposure of T-cells specifically inhibits store operated Ca2+ influx. This may affect gene activation and contribute to the poor T-cell function in chronic inflammatory disease. 相似文献
20.
Xiao-Ying Tien Christopher Katnik Bahaa M. Qasawa Michael D. Sitrin Deborah J. Nelson Thomas A. Brasitus 《The Journal of membrane biology》1993,136(2):159-168
The present studies were conducted to investigate the mechanisms underlying the 1,25-dihydroxycholecalciferol (1,25(OH)2D3)-induced increase in intracellular Ca2+ ([Ca2+]
i
) in individual CaCo-2 cells. In the presence of 2mm Ca2+, 1,25(OH)2D3-induced a rapid transient rise in [Ca2+]
i
in Fura-2-loaded cells in a concentration-dependent manner, which decreased, but did not return to baseline levels. In Ca2+-free buffer, this hormone still induced a transient rise in [Ca2+]
i
, although of lower magnitude, but [Ca2+]
i
then subsequently fell to baseline. In addition, 1,25(OH)2D3 also rapidly induced45Ca uptake by these cells, indicating that the sustained rise in [Ca2+]
i
was due to Ca2+ entry. In Mn2+-containing solutions, 1,25(OH)2D3 increased the rate of Mn2+ influx which was temporally preceded by an increase in [Ca2+]
i
. The sustained rise in [Ca2+]
i
was inhibited in the presence of external La3+ (0.5mm). 1,25(OH)2D3 did not increase Ba2+ entry into the cells. Moreover, neither high external K+ (75mm), nor the addition of Bay K 8644 (1 μm), an L-type, voltage-dependent Ca2+ channel agonist, alone or in combination, were found to increase [Ca2+]
i
, 1,25(OH)2D3 did, however, increase intracellular Na+ in the absence, but not in the presence of 2mm Ca2+, as assessed by the sodium-sensitive dye, sodium-binding benzofuran isophthalate. These data, therefore, indicate that CaCo-2
cells do not express L-type, voltage-dependent Ca2+ channels. 1,25(OH)2D3 does appear to activate a La3+-inhibitable, cation influx pathway in CaCo-2 cells. 相似文献