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1.
Many agonists bring about their effects on cellular functions through a rise incytosolic [Ca2+]([Ca2+]c) mediated by the second messenger inositol 1,4,5-trisphosphate (IP3). Imaging studiesof single cells have demonstrated that [Ca2+]c signals display cell specific spatiotemporalorganization that is established by coordinated activation of IP3 receptor Ca2+ channels.Evidence emerges that cytosolic calcium signals elicited by activation of the IP3 receptors areefficiently transmitted to the mitochondria. An important function of mitochondrial calciumsignals is to activate the Ca2+-sensitive mitochondrial dehydrogenases, and thereby to meetdemands for increased energy in stimulated cells. Activation of the permeability transitionpore (PTP) by mitochondrial calcium signals may also be involved in the control of cell death.Furthermore, mitochondrial Ca2+ transport appears to modulate the spatiotemporal organizationof [Ca2+]c responses evoked by IP3 and so mitochondria may be important in cytosolic calciumsignaling as well. This paper summarizes recent research to elucidate the mechanisms andsignificance of IP3-dependent mitochondrial calcium signaling.  相似文献   

2.
Cytoplasmic Ca2+ is a master regulator of airway physiology; it controls fluid, mucus, and antimicrobial peptide secretion, ciliary beating, and smooth muscle contraction. The focus of this review is on the role of cytoplasmic Ca2+ in fluid secretion by airway exocrine secretory cells. Airway submucosal gland serous acinar cells are the primary fluid secreting cell type of the cartilaginous conducting airways, and this review summarizes the current state of knowledge of the molecular mechanisms of serous cell ion transport, with an emphasis on their regulation by intracellular Ca2+. Many neurotransmitters that regulate secretion from serous acinar cells utilize Ca2+ as a second messenger. Changes in intracellular Ca2+ concentration regulate the activities of ion transporters and channels involved in transepithelial ion transport and fluid secretion, including Ca2+-activated K+ channels and Cl channels. We also review evidence of interactions of Ca2+ signaling with other signaling pathways (cAMP, NO) that impinge upon different ion transport pathways, including the cAMP/PKA-activated cystic fibrosis (CF) transmembrane conductance regulator (CFTR) anion channel. A better understanding of Ca2+ signaling and its targets in airway fluid secretion may identify novel strategies to intervene in airway diseases, for example to enhance fluid secretion in CF airways.  相似文献   

3.
ICa-gated Ca2+ release (CICR) from the cardiac SR is the main mechanism mediating the rise of cytosolic Ca2+, but the extent to which mitochondria contribute to the overall Ca2+ signaling remains controversial. To examine the possible role of mitochondria in Ca2+ signaling, we developed a low affinity mitochondrial Ca2+ probe, mitycam-E31Q (300–500 MOI, 48–72 h) and used it in conjunction with Fura-2AM to obtain simultaneous TIRF images of mitochondrial and cytosolic Ca2+ in cultured neonatal rat cardiomyocytes. Mitycam-E31Q staining of adult feline cardiomyocytes showed the typical mitochondrial longitudinal fluorescent bandings similar to that of TMRE staining, while neonatal rat cardiomyocytes had a disorganized tubular or punctuate appearance. Caffeine puffs produced rapid increases in cytosolic Ca2+ while simultaneously measured global mitycam-E31Q signals decreased more slowly (increased mitochondrial Ca2+) before decaying to baseline levels. Similar, but oscillating mitycam-E31Q signals were seen in spontaneously pacing cells. Withdrawal of Na+ increased global cytosolic and mitochondrial Ca2+ signals in one population of mitochondria, but unexpectedly decreased it (release of Ca2+) in another mitochondrial population. Such mitochondrial Ca2+ release signals were seen not only during long lasting Na+ withdrawal, but also when Ca2+ loaded cells were exposed to caffeine-puffs, and during spontaneous rhythmic beating. Thus, mitochondrial Ca2+ transients appear to activate with a delay following the cytosolic rise of Ca2+ and show diversity in subpopulations of mitochondria that could contribute to the plasticity of mitochondrial Ca2+ signaling.  相似文献   

4.
Local Ca2+ transfer between adjoining domains of the sarcoendoplasmic reticulum (ER/SR) and mitochondria allows ER/SR Ca2+ release to activate mitochondrial Ca2+ uptake and to evoke a matrix [Ca2+] ([Ca2+]m) rise. [Ca2+]m exerts control on several steps of energy metabolism to synchronize ATP generation with cell function. However, calcium signal propagation to the mitochondria may also ignite a cell death program through opening of the permeability transition pore (PTP). This occurs when the Ca2+ release from the ER/SR is enhanced or is coincident with sensitization of the PTP. Recent studies have shown that several pro-apoptotic factors, including members of the Bcl-2 family proteins and reactive oxygen species (ROS) regulate the Ca2+ sensitivity of both the Ca2+ release channels in the ER and the PTP in the mitochondria. To test the relevance of the mitochondrial Ca2+ accumulation in various apoptotic paradigms, methods are available for buffering of [Ca2+], for dissipation of the driving force of the mitochondrial Ca2+ uptake and for inhibition of the mitochondrial Ca2+ transport mechanisms. However, in intact cells, the efficacy and the specificity of these approaches have to be established. Here we discuss mechanisms that recruit the mitochondrial calcium signal to a pro-apoptotic cascade and the approaches available for assessment of the relevance of the mitochondrial Ca2+ handling in apoptosis. We also present a systematic evaluation of the effect of ruthenium red and Ru360, two inhibitors of mitochondrial Ca2+ uptake on cytosolic [Ca2+] and [Ca2+]m in intact cultured cells.  相似文献   

5.
Changes in cytosolic free Ca2+ concentration ([Ca2+]c) play a crucial role in the control of insulin secretion from the electrically excitable pancreatic β-cell. Secretion is controlled by the finely tuned balance between Ca2+ influx (mainly through voltage-dependent Ca2+ channels, but also through voltage-independent Ca2+ channels like store-operated channels) and efflux pathways. Changes in [Ca2+]c directly affect [Ca2+] in various organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus, secretory granules and lysosomes, as imaged using recombinant targeted probes. Because most of these organelles have specific Ca2+ influx and efflux pathways, they mutually influence free [Ca2+] in the others. In this article, we review the mechanisms of control of [Ca2+] in various compartments and particularly the cytosol, the endoplasmic reticulum ([Ca2+]ER), acidic stores and mitochondrial matrix ([Ca2+]mito), focusing chiefly on the most important physiological stimulus of β-cells, glucose. We also briefly review some alterations of β-cell Ca2+ homeostasis in Type 2 diabetes.  相似文献   

6.
It is well established that intracellular calcium ([Ca2+]i) controls the inotropic state of the myocardium, and evidence mounts that a “Ca2+ clock” controls the chronotropic state of the heart. Recent findings describe a calcium-activated nonselective cation channel (NSCCa) in various cardiac preparations sharing hallmark characteristics of the transient receptor potential melastatin 4 (TRPM4). TRPM4 is functionally expressed throughout the heart and has been implicated as a NSCCa that mediates membrane depolarization. However, the functional significance of TRPM4 in regards to Ca2+ signaling and its effects on cellular excitability and pacemaker function remains inconclusive. Here, we show by Fura2 Ca-imaging that pharmacological inhibition of TRPM4 in HL-1 mouse cardiac myocytes by 9-phenanthrol (10 μM) and flufenamic acid (10 and 100 μM) decreases Ca2+ oscillations followed by an overall increase in [Ca2+]i. The latter occurs also in HL-1 cells in Ca2+-free solution and after depletion of sarcoplasmic reticulum Ca2+ with thapsigargin (10 μM). These pharmacologic agents also depolarize HL-1 cell mitochondrial membrane potential. Furthermore, by on-cell voltage clamp we show that 9-phenanthrol reversibly inhibits membrane current; by fluorescence immunohistochemistry we demonstrate that HL-1 cells display punctate surface labeling with TRPM4 antibody; and by immunoblotting using this antibody we show these cells express a 130–150 kDa protein, as expected for TRPM4. We conclude that 9-phenanthrol inhibits TRPM4 ion channels in HL-1 cells, which in turn decreases Ca2+ oscillations followed by a compensatory increase in [Ca2+]i from an intracellular store other than the sarcoplasmic reticulum. We speculate that the most likely source is the mitochondrion.  相似文献   

7.
Proto-oncogenes and tumor suppressors critically control cell-fate decisions like cell survival, adaptation and death. These processes are regulated by Ca2 + signals arising from the endoplasmic reticulum, which at distinct sites is in close proximity to the mitochondria. These organelles are linked by different mechanisms, including Ca2 +-transport mechanisms involving the inositol 1,4,5-trisphosphate receptor (IP3R) and the voltage-dependent anion channel (VDAC). The amount of Ca2 + transfer from the endoplasmic reticulum to mitochondria determines the susceptibility of cells to apoptotic stimuli. Suppressing the transfer of Ca2 + from the endoplasmic reticulum to the mitochondria increases the apoptotic resistance of cells and may decrease the cellular responsiveness to apoptotic signaling in response to cellular damage or alterations. This can result in the survival, growth and proliferation of cells with oncogenic features. Clearly, proper maintenance of endoplasmic reticulum Ca2 + homeostasis and dynamics including its links with the mitochondrial network is essential to detect and eliminate altered cells with oncogenic features through the apoptotic pathway. Proto-oncogenes and tumor suppressors exploit the central role of Ca2 + signaling by targeting the IP3R. There are an increasing number of reports showing that activation of proto-oncogenes or inactivation of tumor suppressors directly affects IP3R function and endoplasmic reticulum Ca2 + homeostasis, thereby decreasing mitochondrial Ca2 + uptake and mitochondrial outer membrane permeabilization. In this review, we provide an overview of the current knowledge on the proto-oncogenes and tumor suppressors identified as IP3R-regulatory proteins and how they affect endoplasmic reticulum Ca2 + homeostasis and dynamics.  相似文献   

8.
The effect of taurine on the ATP-dependent mitochondrial swelling that characterizes the activity of mitochondrial ATP-dependent K+ channel and the formation of Ca2+-dependent pores, different in sensitivity to cyclosporin A, has been studied in rat liver mitochondria. It has been shown that taurine in micromolar concentrations (0.5–125 μM) stimulates the energy-dependent swelling of mitochondria. Taurine in physiological concentrations (0.5–20 mM) has no effect on the ATP-dependent swelling and the formation of cyclosporin A-insensitive Pal/Ca2+-activated pore in mitochondria. Taurine in these concentrations increased the rate of cyclosporin A-sensitive swelling of mitochondria induced by Ca2+ and Pi and reduced the Ca2+ capacity of mitochondria. The different effects of physiological taurine concentrations on the ATP-dependent transport of K+ and Ca2+ ions in mitochondrial membranes as compared with cell membranes are discussed.  相似文献   

9.
Ole H. Petersen   《Cell calcium》2003,33(5-6):337
Studies of Ca2+ transport pathways in exocrine gland cells have been useful, chiefly because of the polarized nature of the secretory epithelial cells. In pancreatic acinar cells, for example, Ca2+ reloading of empty intracellular stores can occur solely via Ca2+ entry through the basal part of the plasma membrane. On the other hand, the principal site for intracellular Ca2+ release—with the highest concentration of inositol 1,4,5-trisphosphate (IP3) receptors—is in the apical secretory pole close to the apical plasma membrane. This apical part of the plasma membrane contains the highest density of Ca2+ pumps and is therefore the principal site for Ca2+ extrusion. On the basis of the known properties of Ca2+ entry and exit pathways in exocrine gland cells, the mechanisms controlling Ca2+ exit and entry are discussed in relation to recent direct information about Ca2+ transport into and out of the endoplasmic reticulum (ER) and the mitochondria in these cells.  相似文献   

10.
Ductal epithelial cells of the exocrine pancreas secrete HCO3 rich, alkaline pancreatic juice, which maintains the intraluminal pH and washes the digestive enzymes out from the ductal system. Importantly, damage of this secretory process can lead to pancreatic diseases such as acute and chronic pancreatitis. Intracellular Ca2+ signaling plays a central role in the physiological regulation of HCO3 secretion, however uncontrolled Ca2+ release can lead to intracellular Ca2+ overload and toxicity, including mitochondrial damage and impaired ATP production. Recent findings suggest that the most common pathogenic factors leading to acute pancreatitis, such as bile acids, or ethanol and ethanol metabolites can evoke different types of intracellular Ca2+ signals, which can stimulate or inhibit ductal HCO3 secretion. Therefore, understanding the intracellular Ca2+ pathways and the mechanisms which can switch a good signal to a bad signal in pancreatic ductal epithelial cells are crucially important. This review summarizes the variety of Ca2+ signals both in physiological and pathophysiological aspects and highlight molecular targets which may strengthen our old friend or release our nasty enemy.  相似文献   

11.
Calcium signaling system in plants   总被引:4,自引:0,他引:4  
  相似文献   

12.
Modulation of calcium signalling by mitochondria   总被引:1,自引:0,他引:1  
Ciara Walsh 《BBA》2009,1787(11):1374-1382
In this review we will attempt to summarise the complex and sometimes contradictory effects that mitochondria have on different forms of calcium signalling. Mitochondria can influence Ca2+ signalling indirectly by changing the concentration of ATP, NAD(P)H, pyruvate and reactive oxygen species — which in turn modulate components of the Ca2+ signalling machinery i.e. buffering, release from internal stores, influx from the extracellular solution, uptake into cellular organelles and extrusion by plasma membrane Ca2+ pumps. Mitochondria can directly influence the calcium concentration in the cytosol of the cell by importing Ca2+ via the mitochondrial Ca2+ uniporter or transporting Ca2+ from the interior of the organelle into the cytosol by means of Na+/Ca2+ or H+/Ca2+ exchangers. Considerable progress in understanding the relationship between Ca2+ signalling cascades and mitochondrial physiology has been accumulated over the last few years due to the development of more advanced optical techniques and electrophysiological approaches.  相似文献   

13.
Sergio de la Fuente 《BBA》2010,1797(10):1727-1735
We have investigated the kinetics of mitochondrial Ca2+ influx and efflux and their dependence on cytosolic [Ca2+] and [Na+] using low-Ca2+-affinity aequorin. The rate of Ca2+ release from mitochondria increased linearly with mitochondrial [Ca2+] ([Ca2+]M). Na+-dependent Ca2+ release was predominant al low [Ca2+]M but saturated at [Ca2+]M around 400 μM, while Na+-independent Ca2+ release was very slow at [Ca2+]M below 200 μM, and then increased at higher [Ca2+]M, perhaps through the opening of a new pathway. Half-maximal activation of Na+-dependent Ca2+ release occurred at 5-10 mM [Na+], within the physiological range of cytosolic [Na+]. Ca2+ entry rates were comparable in size to Ca2+ exit rates at cytosolic [Ca2+] ([Ca2+]c) below 7 μM, but the rate of uptake was dramatically accelerated at higher [Ca2+]c. As a consequence, the presence of [Na+] considerably reduced the rate of [Ca2+]M increase at [Ca2+]c below 7 μM, but its effect was hardly appreciable at 10 μM [Ca2+]c. Exit rates were more dependent on the temperature than uptake rates, thus making the [Ca2+]M transients to be much more prolonged at lower temperature. Our kinetic data suggest that mitochondria have little high affinity Ca2+ buffering, and comparison of our results with data on total mitochondrial Ca2+ fluxes indicate that the mitochondrial Ca2+ bound/Ca2+ free ratio is around 10- to 100-fold for most of the observed [Ca2+]M range and suggest that massive phosphate precipitation can only occur when [Ca2+]M reaches the millimolar range.  相似文献   

14.
15.
Respiring rat liver mitochondria are known to spontaneously release the Ca2+ taken up when they have accumulated Ca2+ over a certain threshold, while Sr2+ and Mn2+ are well tolerated and retained. We have studied the interaction of Sr2+ with Ca2+ release. When Sr2+ was added to respiring mitochondria simultaneously with or soon after the addition of Ca2+, the release was potently inhibited or reversed. On the other hand, when Sr2+ was added before Ca2+, the release was stimulated. Ca2+-induced mitochondrial damage and release of accumulated Ca2+ is generally believed to be due to activation of mitochondrial phospholipase A (EC 3.1.1.4.) by Ca2+. However, isolated mitochondrial phospholipase A activity was little if at all inhibited by Sr2+. The Ca2+ -release may thus be triggered by some Ca2+ -dependent function other than phospholipase.  相似文献   

16.
In the genetic disease cystic fibrosis (CF), the most common mutation F508del promotes the endoplasmic reticulum (ER) retention of misfolded CF proteins. Furthermore, in homozygous F508del-CFTR airway epithelial cells, the histamine Ca2+ mobilization is abnormally increased. Because the uptake of Ca2+ by mitochondria during Ca2+ influx or Ca2+ release from ER stores may be crucial for maintaining a normal Ca2+ homeostasis, we compared the mitochondria morphology and distribution by transmission electron microscopy technique and the mitochondria membrane potential variation (ΔΨmit) using a fluorescent probe (TMRE) on human CF (CF-KM4) and non-CF (MM39) tracheal serous gland cell lines. Confocal imaging of Rhod-2–AM-loaded or of the mitochondrial targeted cameleon 4mtD3cpv-transfected human CF and non-CF cells, were used to examine the ability of mitochondria to sequester intracellular Ca2+. The present study reveals that (i) the mitochondria network is fragmented in F508del-CFTR cells, (ii) the ΔΨmit of CF mitochondria is depolarized compared non-CF mitochondria, and (iii) the CF mitochondria Ca2+ uptake is reduced compared non-CF cells. We propose that these defects in airway epithelial F508del-CFTR cells are the consequence of mitochondrial membrane depolarization leading to a deficient mitochondrial Ca2+ uptake.  相似文献   

17.
The salivary acinar cells have unique Ca2+ signaling machinery that ensures an extensive secretion. The agonist-induced secretion is governed by Ca2+ signals originated from the endoplasmic reticulum (ER) followed by a store-operated Ca2+ entry (SOCE). During tasting and chewing food a frequency of parasympathetic stimulation increases up to ten fold, entailing cells to adapt its Ca2+ machinery to promote ER refilling and ensure sustained SOCE by yet unknown mechanism. By employing a combination of fluorescent Ca2+ imaging in the cytoplasm and inside cellular organelles (ER and mitochondria) we described the role of mitochondria in adjustment of Ca2+ signaling regime and ER refilling according to a pattern of agonist stimulation. Under the sustained stimulation, SOCE is increased proportionally to the degree of ER depletion. Cell adapts its Ca2+ handling system directing more Ca2+ into mitochondria via microdomains of high [Ca2+] providing positive feedback on SOCE while intra-mitochondrial tunneling provides adequate ER refilling. In the absence of an agonist, the bulk of ER refilling occurs through Ca2+-ATPase-mediated Ca2+ uptake within subplasmalemmal space. In conclusion, mitochondria play a key role in the maintenance of sustained SOCE and adequate ER refilling by regulating Ca2+ fluxes within the cell that may represent an intrinsic adaptation mechanism to ensure a long-lasting secretion.  相似文献   

18.
Mitochondria in Ca2+ Signaling and Apoptosis   总被引:8,自引:0,他引:8  
Cellular Ca2+ signals are crucial in the control of most physiological processes, cell injuryand programmed cell death; mitochondria play a pivotal role in the regulation of such cytosolicCa2+ ([Ca2+]c) signals. Mitochondria are endowed with multiple Ca2+ transport mechanismsby which they take up and release Ca2+ across their inner membrane. These transport processesfunction to regulate local and global [Ca2+]c, thereby regulating a number of Ca2+-sensitivecellular mechanisms. The permeability transition pore (PTP) forms the major Ca2+ effluxpathway from mitochondria. In addition, Ca2+ efflux from the mitochondrial matrix occursby the reversal of the uniporter and through the inner membrane Na+/Ca2+ exchanger. Duringcellular Ca2+ overload, mitochondria take up [Ca2+]c, which, in turn, induces opening of PTP,disruption of mitochondrial membrane potential (m) and cell death. In apoptosis signaling,collapse of ;m and cytochrome c release from mitochondria occur followed by activationof caspases, DNA fragmentation, and cell death. Translocation of Bax, an apoptotic signalingprotein from the cytosol to the mitochondrial membrane, is another step during thisapoptosis-signaling pathway. The role of permeability transition in the context of cell death in relationto Bcl-2 family of proteins is discussed.  相似文献   

19.
The amount of Ca2+ taken up in the mitochondrial matrix is a crucial determinant of cell fate; it plays a decisive role in the choice of the cell between life and death. The Ca2+ ions mainly originate from the inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ stores of the endoplasmic reticulum (ER). The uptake of these Ca2+ ions in the mitochondria depends on the functional properties and the subcellular localization of the IP3 receptor (IP3R) in discrete domains near the mitochondria. To allow for an efficient transfer of the Ca2+ ions from the ER to the mitochondria, structural interactions between IP3Rs and mitochondria are needed. This review will focus on the key proteins involved in these interactions, how they are regulated, and what are their physiological roles in apoptosis, necrosis and autophagy. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.  相似文献   

20.
Using complementary luminescent- and fluorescent-based Ca2+ imaging techniques, we have re-examined the Ca2+ dynamics that occur during the Blastula Period (BP) of zebrafish development. We confirm that aperiodic, localized Ca2+ transients are generated predominately in the superficial epithelial cells (SECs). At the start of the BP, these Ca2+ transients are distributed homogeneously throughout the entire superficial epithelium. Following the mid-blastula transition (MBT), however, their distribution becomes asymmetrical, where a significantly greater number are generated in the presumptive dorsal quadrant of the superficial epithelium. This asymmetry in Ca2+ signaling lasts for around 60 min, after which the total number of transients generated from the entire superficial epithelium falls to less than one per minute until the end of the BP. We have thus called this asymmetry the “dorsal-biased Ca2+ signaling window”. The application of pharmacological agents indicates that the post-MBT SEC Ca2+ transients are generated via the phosphatidylinositol (PI) signaling pathway. This suggests that the previously reported ventralizing function attributed to the homogeneously distributed PI pathway-generated SEC Ca2+ transients is most likely to occur earlier in development, prior to the MBT.  相似文献   

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