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1.
Pancreatitis, a potentially fatal disease in which the pancreas digests itself as well as its surroundings, is a well recognized complication of hyperlipidemia. Fatty acids have toxic effects on pancreatic acinar cells and these are mediated by large sustained elevations of the cytosolic Ca2+ concentration. An important component of the effect of fatty acids is due to inhibition of mitochondrial function and subsequent ATP depletion, which reduces the operation of Ca2+-activated ATPases in both the endoplasmic reticulum and the plasma membrane. One of the main causes of pancreatitis is alcohol abuse. Whereas the effects of even high alcohol concentrations on isolated pancreatic acinar cells are variable and often small, fatty acid ethyl esters – synthesized by combination of alcohol and fatty acids – consistently evoke major Ca2+ release from intracellular stores, subsequently opening Ca2+ entry channels in the plasma membrane. The crucial trigger for pancreatic autodigestion is intracellular trypsin activation. Although there is still uncertainty about the exact molecular mechanism by which this Ca2+-dependent process occurs, progress has been made in identifying a subcellular compartment – namely acid post-exocytotic endocytic vacuoles – in which this activation takes place.  相似文献   

2.
There is growing evidence that intracellular calcium plays a primary role in the pathophysiology of the pancreas in addition to its crucial importance in major physiological functions. Pancreatic acinar cells have a remarkably large amount of Ca2+ stored in both the endoplasmic reticulum (ER) and the acidic stores. The vast majority of the classical ER Ca2+ store is located in the basal part of the acinar cells with extensions protruding into the apical area, however, the acidic stores are exclusively located in the secretory granular area of the cells. Both types of Ca2+ store respond to all three intracellular Ca2+ messengers – inositol trisphosphate (InsP3), cyclic-ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). The two stores interact with each other via calcium-induced calcium release; however, they can be separated using pharmacological tools. The ER relies on sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) that can be blocked by the specific inhibitor thapsigargin. The acidic store requires a low pH that can be modified by blocking vacuolar H+-ATPase.  相似文献   

3.
Evidence for a primary role for intracellular Ca2+ in the stimulation of pancreatic enzyme secretion is reviewed. Measurements of cytoplasmic free Ca2+ concentration have allowed direct demonstration of its importance in triggering enzyme secretion and defined the concentration range over which membrane Ca2+ pumps must work to regulate intracellular Ca2+. Current evidence suggests a key role for the Ca2+ Mg-ATPase of rough endoplasmic reticulum in regulating intracellular Ca2+ and accumulating a Ca2+ store which is released by the action of inositol-l,4,5 trisphosphate following stimulation of secretion.Abbreviations Used EGTA (ethylene dioxy) diethylene-dinitrilotetraacetic acid - BAPTA 1,2-bis (2-aminophenoxy) ethane NNN,N-tetracetic acid - InsP3 inositol trisphosphate - Ins-1,4,5P3 and Ins-1,3,4P3 isomers of inositol trisphosphate with the position of phosphate groups assigned - Ins-1,3,4,5P4 inositol tetrakisphosphate  相似文献   

4.
《Cell calcium》2007,41(5-6):593-600
Normal physiological regulation depends on Ca2+ microdomains, because there is a need to spatially separate Ca2+ regulation of different cellular processes. It is only possible to generate local Ca2+ signals transiently; so, there is an important functional link between Ca2+ spiking and microdomains. The pancreatic acinar cell provides a useful cell biological model, because of its clear structural and functional polarization. Although local Ca2+ spiking in the apical (granular) microdomain regulates fluid and enzyme secretion, prolonged global elevations of the cytosolic Ca2+ concentration are associated with the human disease acute pancreatitis, in which proteases in the granular region become inappropriately activated and digest the pancreas and its surroundings. A major cause of pancreatitis is alcohol abuse and it has now been established that fatty acid ethyl esters and fatty acids, non-oxidative alcohol metabolites, are principally responsible for causing the acinar cell damage. The fatty acid ethyl esters release Ca2+ from the endoplasmic reticulum and the fatty acids inhibit markedly mitochondrial ATP generation, which prevents the acinar cell from disposing of the excess Ca2+ in the cytosol. Because of the abolition of ATP-dependent Ca2+ pump activity, all intracellular Ca2+ concentration gradients disappear and the most important part of the normal regulatory machinery is thereby destroyed. The end stage is necrosis.  相似文献   

5.
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   

6.
Patel S  Muallem S 《Cell calcium》2011,50(2):109-112
Changes in the concentration of cytosolic Ca2+ form the basis of a ubiquitous signal transduction pathway. Accumulating evidence implicates acidic organelles in the control of Ca2+ dynamics in organisms across phyla. In this special issue, we discuss Ca2+ signalling by these “acidic Ca2+ stores” which include acidocalcisomes, vacuoles, the endo-lysosomal system, lysosome-related organelles, secretory vesicles and the Golgi complex. Ca2+ release from these morphologically very different organelles is mediated by members of the TRP channel superfamily and two-pore channels. Inositol trisphosphate and ryanodine receptors which are traditionally viewed as endoplasmic reticulum Ca2+ release channels can also mobilize acidic Ca2+ stores. Ca2+ uptake into acidic Ca2+ stores is driven by Ca2+ ATPases and Ca2+/H+ exchangers. In animal cells, the Ca2+-mobilizing messenger NAADP plays a central role in mediating Ca2+ signals from acidic Ca2+ stores through activation of two-pore channels. These signals are important for several physiological processes including muscle contraction and differentiation. Dysfunctional acidic Ca2+ stores have been implicated in diseases such as acute pancreatitis and lysosomal storage disorders. Acidic Ca2+ stores are therefore emerging as essential components of the Ca2+ signalling network and merit extensive further study.  相似文献   

7.
The TRIC channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation-specific channels and likely mediate counterion movements to support efficient Ca2+ release from the sarco/endoplasmic reticulum. Vascular smooth muscle cells (VSMCs) contain both TRIC subtypes and two Ca2+ release mechanisms; incidental opening of ryanodine receptors (RyRs) generates local Ca2+ sparks to induce hyperpolarization and relaxation, whereas agonist-induced activation of inositol trisphosphate receptors produces global Ca2+ transients causing contraction. Tric-a knock-out mice develop hypertension due to insufficient RyR-mediated Ca2+ sparks in VSMCs. Here we describe transgenic mice overexpressing TRIC-A channels under the control of a smooth muscle cell-specific promoter. The transgenic mice developed congenital hypotension. In Tric-a-overexpressing VSMCs from the transgenic mice, the resting membrane potential decreased because RyR-mediated Ca2+ sparks were facilitated and cell surface Ca2+-dependent K+ channels were hyperactivated. Under such hyperpolarized conditions, L-type Ca2+ channels were inactivated, and thus, the resting intracellular Ca2+ levels were reduced in Tric-a-overexpressing VSMCs. Moreover, Tric-a overexpression impaired inositol trisphosphate-sensitive stores to diminish agonist-induced Ca2+ signaling in VSMCs. These altered features likely reduced vascular tonus leading to the hypotensive phenotype. Our Tric-a-transgenic mice together with Tric-a knock-out mice indicate that TRIC-A channel density in VSMCs is responsible for controlling basal blood pressure at the whole-animal level.  相似文献   

8.
Rosado JA 《Cell calcium》2011,50(2):168-174
Changes in cytosolic free Ca2+ concentration play a pivotal role in the regulation of platelet functions, from secretion of autocrine and procoagulant factors to reversible or irreversible aggregation. It has long been recognized that platelet agonists release Ca2+ accumulated into the dense tubular system, the analogue of the endoplasmic reticulum. However, current evidence indicates that Ca2+ can also be stored and released from a number of acidic organelles, including lysosomes and lysosome-related organelles. Ca2+ release from the dense tubular system is mediated through phospholipase C-dependent synthesis of inositol 1,4,5-trisphosphate, whereas Ca2+ efflux from the acidic stores seems to be associated to the second messenger nicotinic acid adenine dinucleotide phosphate. The biochemical and biophysical properties of both Ca2+ stores in platelets have been reported to show significant differences. Selective discharge of one or both stores depends on the platelet agonist and the concentration used, which further supports the complexity of the Ca2+ signals that regulate platelet function. In this paper, we summarize the current knowledge on the role of acidic organelles in agonist-evoked Ca2+ mobilization and highlight recent progress in understanding the functional aspects of the acidic Ca2+ stores in Ca2+ signalling and platelet physiology.  相似文献   

9.
Apoptosis is a highly complex form of cell death that can be triggered by alterations in Ca2+ homeostasis. Members of the Bcl-2 family may regulate apoptosis and modulate Ca2+ distribution within intracellular compartments. Bax, a proapoptotic member of the family, is constitutively expressed and soluble in the cytosol and, under apoptotic induction, translocates to mitochondrial membranes. However, it is not clear if the intracellular Ca2+ stores and selective Ca2+ releases can modulate or control Bax translocation. The aim of this study was to investigate the relation of intracellular Ca2+ stores with Bax translocation in rat cortical astrocytes. Results show that the classical apoptotic inducer, staurosporine, caused high elevations of cytosolic Ca2+ that precede Bax translocation. On the other hand, agents that mobilize Ca2+ from endoplasmic reticulum such as noradrenaline or thapsigargin, induced Bax translocation, while mitochondrial Ca2+ release evoked by carbonyl cyanide-p-(trifluoromethoxyphenyl) hydrazone was not able to cause Bax punctation. In addition, microinjection of inositol 1,4,5- trisphosphate induced Bax translocation. Taken together, our results show that in Bax overexpressing cortical astrocytes, endoplasmic reticulum-Ca2+ release may induce Bax transactivation and specifically control apoptosis.  相似文献   

10.
A theoretical model of calcium signaling is presented that simulates oscillations of cytoplasmic calcium concentration ([Ca2+]cyt) in stomatal guard cells under the action of abscisic acid. The model is based on the kinetics of inositol 1,4,5-trisphosphate-sensitive calcium channels of endoplasmic reticulum and cyclic ADP-ribose-sensitive calcium channels of the tonoplast. The operation of two energy-dependent pumps—the Ca2+-ATPase of the endoplasmic reticulum and the Ca2+/H+ antiporter of the tonoplast—is also included in the model. It is shown that the removal of excessive Ca2+ from the cytoplasm by the tonoplast Ca2+/H+ antiporter is the main factor accounting for generation of [Ca2+]cyt oscillations at a wide range of ABA concentrations (0.01–1 M). The long period of [Ca2+]cyt oscillations in plant cells is explained by a slow release from inhibition of inositol 1,4,5-trisphosphate-gated calcium channels.  相似文献   

11.
Homer proteins are scaffold molecules with a domain structure consisting of an N-terminal Ena/VASP homology 1 protein-binding domain and a C-terminal leucine zipper/coiled-coil domain. The Ena/VASP homology 1 domain recognizes proline-rich motifs and binds multiple Ca2+-signaling proteins, including G protein-coupled receptors, inositol 1,4,5-triphosphate receptors, ryanodine receptors, and transient receptor potential channels. However, their role in Ca2+ signaling in nonexcitable cells is not well understood. In this study, we investigated the role of Homer2 on Ca2+ signaling in parotid gland acinar cells using Homer2-deficient (Homer2−/−) mice. Homer2 is localized at the apical pole in acinar cells. Deletion of Homer2 did not affect inositol 1,4,5-triphosphate receptor localization or channel activity and did not affect the expression and activity of sarco/endoplasmic reticulum Ca2+-ATPase pumps. In contrast, Homer2 deletion markedly increased expression of plasma membrane Ca2+-ATPase (PMCA) pumps, in particular PMCA4, at the apical pole. Accordingly, Homer2 deficiency increased Ca2+ extrusion by acinar cells. These findings were supported by co-immunoprecipitation of Homer2 and PMCA in wild-type parotid cells and transfected human embryonic kidney 293 (HEK293) cells. We identified a Homer-binding PPXXF-like motif in the N terminus of PMCA that is required for interaction with Homer2. Mutation of the PPXXF-like motif did not affect the interaction of PMCA with Homer1 but inhibited its interaction with Homer2 and increased Ca2+ clearance by PMCA. These findings reveal an important regulation of PMCA by Homer2 that has a central role on PMCA-mediated Ca2+ signaling in parotid acinar cells.  相似文献   

12.
Calcium signaling by cyclic ADP-ribose and NAADP   总被引:4,自引:0,他引:4  
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   

13.
Abstract. The albumen gland of the freshwater pulmonate snail Helisoma duryi produces and secretes the perivitelline fluid, which coats fertilized eggs and provides nutrients to the developing embryos. It is known that perivitelline fluid secretion is stimulated by dopamine through the activation of a dopamine D1‐like receptor, which in turn stimulates cAMP production leading to the secretion of perivitelline fluid. This paper examines the glandular release of perivitelline fluid and provides evidence for the role of Ca2+ in the regulated secretion of perivitelline fluid based on protein secretion experiments and inositol 1,4,5‐trisphosphate assays. Dopamine‐stimulated protein secretion by the albumen gland is reduced in Ca2+‐free medium or in the presence of plasma membrane Ca2+ channel blockers, although the Ca2+ channel subtype involved is unclear. In addition, dopamine‐stimulated protein secretion does not directly involve phospholipase C‐generated signaling pathways and Ca2+ release from intracellular stores. Sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase inhibitors had little effect on protein secretion when applied alone; however, they potentiated dopamine‐stimulated protein secretion. Dantrolene, an inhibitor of ryanodine receptors, 8‐(N,N‐diethylamino)‐octyl‐3,4,5‐trimethoxybenzoate hydrochloride, a nonspecific inhibitor of intracellular Ca2+ channels, and 2‐aminoethyldiphenylborate, an inhibitor of inositol 1,4,5‐trisphosphate receptors, did not suppress protein secretion, suggesting Ca2+ release from internal stores does not directly regulate protein secretion. Thus, the influx of Ca2+ from the extracellular space appears to be the major pathway mediating protein secretion by the albumen gland. The results are discussed with respect to the role of Ca2+ in controlling exocytosis of proteins from the albumen gland secretory cells.  相似文献   

14.
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   

15.

Background  

cAMP-induced Ca2+-influx in Dictyostelium is controlled by at least two non-mitochondrial Ca2+-stores: acidic stores and the endoplasmic reticulum (ER). The acidic stores may comprise the contractile vacuole network (CV), the endosomal compartment and acidocalcisomes. Here the role of CV in respect to function as a potential Ca2+-store was investigated.  相似文献   

16.
ITPRs (inositol 1,4,5-trisphosphate receptors), the main endoplasmic reticulum (ER) Ca2+-release channels, were originally proposed as suppressors of autophagy. Yet, new evidence has accumulated over recent years supporting a crucial, stimulatory role for ITPRs in driving the autophagic flux. Here, we provide an integrated view on how ITPR-mediated Ca2+ signaling can have a dual impact on autophagy, depending on the characteristics of the spatio-temporal Ca2+ signals, including the existence of ER-mitochondrial and ER-lysosomal Ca2+ signaling microdomains.  相似文献   

17.

Background

A novel family of intracellular Ca2+-release channels termed two-pore channels (TPCs) has been presented as the receptors of NAADP (nicotinic acid adenine dinucleotide phosphate), the most potent Ca2+ mobilizing intracellular messenger. TPCs have been shown to be exclusively localized to the endolysosomal system mediating NAADP-evoked Ca2+ release from the acidic compartments.

Objectives

The present study is aimed to investigate NAADP-mediated Ca2+ release from intracellular stores in the megakaryoblastic cell line MEG01.

Methods

Changes in cytosolic and intraluminal free Ca2+ concentrations were registered by fluorimetry using fura-2 and fura-ff, respectively; TPC expression was detected by PCR.

Results

Treatment of MEG01 cells with the H+/K+ ionophore nigericin or the V-type H+-ATPase selective inhibitor bafilomycin A1 revealed the presence of acidic Ca2+ stores in these cells, sensitive to the SERCA inhibitor 2,5-di-(tert-butyl)-1,4-hydroquinone (TBHQ). NAADP releases Ca2+ from acidic lysosomal-like Ca2+ stores in MEG01 cells probably mediated by the activation of TPC1 and TPC2 as demonstrated by TPC1 and TPC2 expression silencing and overexpression. Ca2+ efflux from the acidic lysosomal-like Ca2+ stores or the endoplasmic reticulum (ER) results in ryanodine-sensitive activation of Ca2+-induced Ca2+ release (CICR) from the complementary Ca2+ compartment.

Conclusion

Our results show for the first time NAADP-evoked Ca2+ release from acidic compartments through the activation of TPC1 and TPC2, and CICR, in a megakaryoblastic cell line.  相似文献   

18.
Nicotinic acid dinucleotide phosphate (NAADP) is unique amongst Ca2+ mobilizing messengers in that its principal function is to mobilize Ca2+ from acidic organelles. Early studies indicated that it was likely that NAADP activates a novel Ca2+ release channel distinct from the well characterized Ca2+ release channels on the (sarco)-endoplasmic reticulum (ER), inositol trisphosphate and ryanodine receptors. In this review, we discuss the emergence of a novel family of endolysosomal channels, the two-pore channels (TPCs), as likely targets for NAADP, and how molecular and pharmacological manipulation of these channels is enhancing our understanding of the physiological roles of NAADP as an intracellular Ca2+ mobilizing messenger.  相似文献   

19.
Ca2+ signals propagate in wave form along individual cells of the central nervous system(CNS) and through networks of connected cells of neuronal and multiple glial cell types. Inorder for wave fronts to convey information, signaling mechanisms are required that allowwaves to propagate reproducibly and without decrement in signal strength over long distances.CNS Ca2+ waves are under specific integrated local control, made possible by interactions atlocal subcellular microdomains between endoplasmic reticulum and mitochondria. Activemitochondria located near the mouth of inositol trisphosphate receptor (InsP3R) channel clustersin glia take up Ca2+, which may prevent a buildup of Ca2+ around the InsP3R channel, therebydecreasing the rate of Ca2+-induced receptor inactivation, and prolonging channel open time.Mitochondria may amplify InsP;i3-dependent Ca2;pl signals by a transient permeability transitionin response to Ca2+ uptake into the mitochondrion. Other evidence suggests privileged accessinto mitochondria for Ca2+ entering neurons by glutamatergic receptor channels. This enablesspecific signal modulation as the Ca2+ wave is propagated into neurons, such that mitochondrialocated close to glutamate channels can prolong the neuronal cytosolic response time bysuccessive uptake and release of Ca2+. Disruption of mitochondrial function deregulates theability of CNS-derived cells to undergo normal Ca2+ signaling and wave propagation.  相似文献   

20.
In Xenopus laevis oocytes, overexpression of calreticulin suppresses inositol 1,4,5-trisphosphate-induced Ca2+ oscillations in a manner consistent with inhibition of Ca2+ uptake into the endoplasmic reticulum. Here we report that the alternatively spliced isoforms of the sarcoendoplasmic reticulum Ca2+-ATPase (SERCA)2 gene display differential Ca2+ wave properties and sensitivity to modulation by calreticulin. We demonstrate by glucosidase inhibition and site-directed mutagenesis that a putative glycosylated residue (N1036) in SERCA2b is critical in determining both the selective targeting of calreticulin to SERCA2b and isoform functional differences. Calreticulin belongs to a novel class of lectin ER chaperones that modulate immature protein folding. In addition to this role, we suggest that these chaperones dynamically modulate the conformation of mature glycoproteins, thereby affecting their function.  相似文献   

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