Dissertations / Theses: 'Sodium/calcium exchanger (NCX)'

1

Jeffs, Graham J. "The effect of sodium/calcium exchanger 3 (NCX3) knockout on neuronal survival following global cerebral ischaemia in mice." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2007. http://theses.library.uwa.edu.au/adt-WU2008.0063.

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Cerebral ischaemia is a leading cause of disability and death world-wide. The only effective treatments are thrombolytic therapy (plasminogen activator; tPA) and hypothermia (33?C). However, tPA has limited clinical application due to its short therapeutic time window and its specific application in thrombo-embolic stroke. Moderate hypothermia (33?C) is only being used following cardiac arrest in comatose survivors. Hence more treatments are urgently required. The first step in developing new treatments is the identification and characterisation of a potential therapeutic target. Since brain damage following cerebral ischaemia is associated with disturbances in intracellular calcium homeostasis, the sodium-calcium exchanger (NCX) is a potential therapeutic target due to its ability to regulate intracellular calcium. Currently, however there is uncertainty as to whether the plasma membrane NCX has a neuroprotective or neurodamaging role following cerebral ischemia. To address this issue I compared hippocampal neuronal injury in NCX3 knockout mice (Ncx3-/-) and wild-type mice (Ncx3+/+) following global cerebral ischaemia. In order to perform this study I first established a bilateral common carotid occlusion (BCCAO) model of global ischaemia in wild-type C57/BlHsnD mice using controlled ventilation. After trials of several ischaemic time points, 17 minutes was established as the optimum duration of ischaemia to produce selective hippocampal CA1 neuronal loss in the wild-type mice. I then subjected NCX3 knockout and wild-type mice to 17 minutes of ischaemia. Following the 17 minute period of ischaemia, wild-type mice exhibited 80% CA1 neuronal loss and 40% CA2 neuronal loss. In contrast, NCX3 knockout mice displayed > 95% CA1 neuronal loss and 95% CA2 neuronal loss. Following experiments using a 17 minute duration of global ischaemia, a 15 minute duration of ischaemia was also evaluated. Wild-type mice exposed to a 15 minute period of ischaemia, did not exhibit any significant hippocampal neuronal loss. In contrast, NCX3 knockout mice displayed 45% CA1 neuronal loss and 25% CA2 neuronal loss. The results clearly demonstrate that mice deficient for the NCX3 protein are more susceptible to global cerebral ischaemia than wild-type mice. My findings showing a neuroprotective role for NCX3 following ischaemia, suggest that the exchanger has a positive role in maintaining neuronal intracellular calcium homeostasis. When this function is disrupted, neurons are more susceptible to calcium deregulation, with resultant cell death via calcium mediated pathways. Therefore, improving NCX activity following cerebral ischaemia may provide a therapeutic strategy to reduce neuronal death.

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2

Reilly, Louise. "Palmitoylation of the cardiac sodium-calcium exchanger." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/37d8a92d-1536-4a05-85f6-a45f9c41a489.

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3

Sher, Anna. "Modelling local calcium dynamics and the sodium/calcium exchanger in ventricular myocytes." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670114.

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4

Bossuyt, Julie. "Sodium-calcium exchange and caveolins." MU has:, 2002. http://wwwlib.umi.com/cr/mo/fulltext?p3052149.

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5

Han, C. (Chunlei). "Intracellular calcium stores and sodium-calcium exchanger in cardiac myocytes:experimental and computer simulation study." Doctoral thesis, University of Oulu, 2001. http://urn.fi/urn:isbn:9514265912.

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Abstract Cytosolic Ca2+, [Ca2+]I , has a key role in intracellular signalling during excitation-contraction coupling (E-C coupling) in cardiac myocytes. The sarcoplasmic reticulum (SR) is a main intracellular Ca2+ store and the Na+-Ca2+ exchanger (NaCaX) is a major mechanism to extrude Ca2+ for balancing the Ca2+ influx via L-type Ca2+ channels during excitation. Furthermore, [Ca2+]I also affects the configuration of the action potential (AP). The present study, by combination of animal experiments and computer simulations, investigated the roles of [Ca2+]I, SR and NaCaX in cardiac myocytes, in Ca2+-induced Ca2+ release (CICR) and in modulation of APs. The following were studied: (I) the stretch-induced effects on rat atrium and the role of [Ca2+]I in modulation of AP; (II) the role of the SR in modulation in rat atrium by stretch; (III) the role of NaCaX; (IV) the role of [Ca2+]I in modulation of action potential duration (APD) in myocytes with short and long action potential duration. In isolated rat atrial preparations, the physiological or moderate stretch stimulus caused two- phasic rise of developed contraction, rapid and slow phases, accompanied with slow increments of [Ca2+]I and prolongations of action potentials durations in continuous recordings. In sustained stretch, the APD and [Ca2+]I were all increased significantly when intra-atrial pressure increased from 1 to 3 mmHg. In computer simulations, employing a rat atrial model (RA model), it was found that stretch-activated channels and increased Tn C affinity for Ca2+ alone could not produce the changes in the experiments. Only after both mechanisms applied to model cells, the main experimental findings could be mimicked (I). The prolongation of APD induced by stretch in rat atrial preparations was reversed after depleting the Ca2+ content of the SR by application of the SR functional inhibitors, ryanodine, thapsigargin and caffeine (II). In the computer simulation using modified guinea pig ventricular model, the Ca2+ entry via the reversal of NaCaX was found to be accounting 25% of the total activator Ca2+ for triggering Ca2+ release from the SR during normal excitation. This contribution increases with elevated [Na+]i (III). In a guinea pig ventricular model (GPV model) and a RA model were employed for investigating the regulation of APD by [Ca2+]I-dependent membrane currents. Increased SR Ca2+ content produced an elevated [Ca2+]I in both model cells, leading to prolongation of APD in the RA model but shortening in the GPV model. Increased [Ca2+]I enhances the NaCaX current in the same scale in both models, but inhibits L-type Ca current much more in the GPV model than the RA model (IV). In conclusion, (I) Stretch-induced [Ca2+]I increase prolongs the rat atrial AP by enhancing the NaCaX inward current. Stretch-activated channels (SACs) and increased affinity of TnC for Ca2+ are main general factors responsible for the variety of changes of cardiac muscles induced by stretch. (II) The SR plays a crucial role in the modulation of myocytes by accumulating the additional Ca2+ influx via sarcolemma during stretch. (III) The NaCaX contributes a small part for activator Ca2+ for calcium release from the SR during normal cardiac E-C coupling. However, this contribution is [Na]i-dependent, and in some pathological conditions, it may be a potential factor for cardiac arrhythmogenesis. (IV) Different effects on the NaCaX and L-type channels induced by increased [Ca2+]I leads to the dispersion of the change of APD in myocytes with long and short AP during inotropic interventions that increase the [Ca2+]I.

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6

Hung, Hsiao-Yu. "Spatial organization of sodium calcium exchanger and caveolin-3 in developing mammalian ventricular cardiomyocytes." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/791.

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In adult cardiomyocytes, the established mechanism of excitation-contraction coupling is calcium-induced calcium release (CICR) mediated by L-type Ca2+ channels (Cav1.2). Briefly, membrane depolarization opens voltage-gated Cav1.2 to allow for the influx of extracellular Ca2+ into the cytosol. This small sarcolemmal (SL) Ca2+ influx is necessary for triggering a larger release of Ca2+ from the intracellular Ca2+ storage site, the sarcoplasmic reticulum (SR), through the SR Ca2+ release channel also known as the ryanodine receptor (RyR). RyR-mediated release of SR Ca2+ effectively raises the cytosolic free Ca2+ concentration, allowing for Ca2+ binding to troponin C on the troponin-tropomysin complex, leading to cross-bridge formation and cell contraction. However, previous functional data suggests an additional CICR modality involving reverse mode Na+-Ca2+ exchanger (NCX) activity also exists in neonate cardiomyocytes. To further our understanding of how CICR changes occur during development, we investigated the spatial arrangement of caveolin-3 (cav-3), the principle structural protein of small membrane invaginations named caveolae, and NCX in developing rabbit ventricular myocytes. Using traditional as well as novel image processing and analysis techniques, both qualitative and quantitative findings firmly establish the highly robust and organized nature of NCX and cav-3 distributions during development. Specifically, our results show that NCX and cav-3 are distributed on the peripheral membrane as discrete clusters and are not highly colocalized throughout development. 3D distance analysis revealed that NCX and cav-3 clusters are organized with a distinct longitudinal and transverse periodicity of 1-1.5 μm and that NCX and cav-3 cluster have a pronounced tendency to be mutually exclusive on the cell periphery. Although these findings do not support the original hypothesis that caveolae is the structuring element for a restricted microdomain facilitating NCX-CICR, our results cannot rule out the existence of such microdomain organized by other anchoring proteins. The developmentally stable distributions of NCX and cav-3 imply that the observed developmental CICR changes are achieved by the spatial re-organization of other protein partners of NCX or non-spatial modifications. In addition, the newly developed image processing and analysis techniques can have wide applicability to the investigations on the spatial distribution of other proteins and cellular structures.

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7

Modgi, Amol Polo-Parada Luis. "The role of sodium-calcium exchanger in the electrical activity of embryonic chicken heart." Diss., Columbia, Mo. : University of Missouri--Columbia, 2008. http://hdl.handle.net/10355/6671.

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The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on September 25, 2009). Thesis advisor: Dr. Luis Polo Parada. Includes bibliographical references.

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Elliott, Elspeth B. A. "Investigation of factors affecting the sodium/calcium exchanger in a rabbit model of left ventricular dysfunction." Thesis, University of Glasgow, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433518.

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9

Guan, Yinzheng. "Blebbistatin Protects Rodent Myocytes from Death in Primary Culture via Inhibiting the Sodium/ Calcium Exchanger and the L-type Calcium Channel." Master's thesis, Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/150014.

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Physiology
M.S.
Introduction: Cardiac disease is a leading cause of mortabity and morbidity in the developed countries. Cultured cardiac myocytes are widely used for exploring the underlying pathophysiology of cardiac disease. Rodents, especially mice with transgenes or gene ablation, have become popular animal models for heart disease research. However, it has been long recognized that rodent myoyctes die during long-term primary culture, which limits the use of genetically altered myocytes for signaling studies. Blebbistatin (BLB), a myosin II ATPase inhibitor, has been used to protect rodent myocytes. The mechanisms underlying the protective effects of this drug are not clear and are the topics of this study. Materials & methods: Adult rat ventricular myocytes (ARVM) were isolated and cultured with or without BLB (10 µM) for 72 hours in comparison with another protective chemical, BDM (10mM). Myocyte death was evaluated by morphology changes and trypan blue staining. The effects of these two drugs on myocyte contraction, intracellular Ca2+ transient ([Ca2+]i, indo-1,410/480), SR Ca2+ content, L-type calcium and Na+ /Ca2+exchanger currents were studied acutely. Neonatal rat ventricular myocytes (NRVM) were isolated from 1-3 days old neonatal rat hearts and cultured. The effect of BDM (10mM BDM) and BLB (10 µM) in the medium on NRVM growth and hypertrophy induced by norepinephrine (NE, 10µM) were determined. Results: 1. Both BDM and BLB promoted myocyte survival in culture at 72 hours but BLB protected more myocytes (Control: 7.0±1.8% vs. BDM: 61.5±6.4% vs. BLB: 74.0±3.2%); 2. ARVM fractional shortening was reduced by BLB to 1.7±0.4% and by BDM to 0.5±0.1% from the baseline of 6.5±0.7%; 3. Acutely, the amplitude of [Ca2+]i (∆ [Ca2+]i) evaluated with indo-1 AM (F410/F480) was depressed by both BDM (0.04±0.01) and BLB (0.07±0.01) compared to control (0.13±0.01). 4. Diastolic Ca2+ was significantly increased by BLB (0.90±0.06) but not by BDM (0.73±0.06) compared to pre-treat values (0.70±0.05); 5. BLB and BDM significantly reduced the SR Ca2+ content, as indicated by the reduced amplitudes of caffeine-induced Ca2+ transients in BLB- and BDM-treated ARVMs (∆[Ca2+]i in BLB vs. BDM vs. baseline: 0.20±0.03, 0.19±0.04, 0.30±0.03). 6. The mechanisms of the protective effects of BDM and BLB were similar but quantitatively different in that BDM reduced more Ca influx through the L-type Ca2+ channel (ICa-L) than BLB (the reduction in BDM-treated cells vs. BLB-treated cells: 70% vs. 40%) while BLB inhibited more Na+/Ca2+exchanger current (75% inhibition) than BDM (40% reduction); 7. Both BDM and BLB inhibited normal NRVM growth and NE-induced hypertrophy and NFAT translocation in NRVMs. Conclusion: These results suggest both BDM and BLB protect rodent myocytes in culture by preventing cytosolic and SR Ca2+ overload by similar mechanisms: inhibiting NCX and reducing the LTCC. The application of BLB to whole-heart studies and myocyte hypertrophy should be extremely cautioned because BLB does alter myocyte Ca2+ handling.
Temple University--Theses

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10

Yuan, Jiaqi. "Investigations of macromolecules and small biomolecules by solution NMR: applications to the intracellular loop structure of the sodium-calcium exchanger and metabolite identification methods." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1542630633935356.

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11

Nguidjoe, Evrard. "Etude de la fonction de la cellule bêta pancréatique dans un modèle de souris présentant une mutation nulle partielle de l'échangeur sodium/calcium." Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209833.

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Précédemment, nous avons montré que la surexpression de l'échangeur Na/Ca NCX1), une protéine responsable de la sortie de calcium (Ca2+) des cellules, augmentait la mort cellulaire programmée ou « apoptose » et réduisait la prolifération des cellules β. Afin d’étudier plus en profondeur le rôle de l’échangeur dans les cellules β in vivo, nous avons développé et caractérisé des souris présentant une inactivation de NCX1.

Des méthodes biologiques et morphologiques (imagerie du Ca2+, capture de Ca2+, métabolisme du glucose, sécrétion d'insuline et morphométrie par comptage de points) ont été utilisées pour évaluer la fonction de la cellule β in vitro. Les taux de glucose et d'insuline dans le sang ont été mesurés afin de déterminer le métabolisme du glucose et la sensibilité à l’insuline in vivo. Des îlots ont été transplantés sous la capsule rénale pour évaluer leur capacité à corriger le diabète chez les souris rendues diabétiques par l’alloxane.

L'inactivation hétérozygote de Ncx1 chez les souris provoque une augmentation de la sécrétion d’insuline induite par le glucose avec un renforcement important à la fois de la première et de la deuxième phase. Ces résultats s’accompagnent d’une augmentation de la masse et de la prolifération des cellules β. La mutation augmente également le contenu en insuline, l’immunomarquage de la proinsuline, la capture de Ca2+ induite par le glucose et la résistance à l'hypoxie des cellules β. En outre, les îlots de souris Ncx1+/- montrent une capacité à compenser le diabète 2 à 4 fois plus élevé que les îlots de souris Ncx1+/+ lorsque transplantés chez des souris diabétiques.

En conclusion, l’inactivation de l'échangeur Na/Ca conduit à une augmentation de la fonction de la cellule β, de sa prolifération, de sa masse et de sa résistance au stress physiologique, à savoir à divers changements de fonction des cellules β opposés aux principales anomalies rencontrées dans le diabète de type 2 (Type 2 Diabetes Mellitus,T2DM). Ceci nous procure un modèle unique pour la prévention et le traitement du dysfonctionnement des cellules β dans le T2DM et pour la transplantation d'îlots.

Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

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12

Vierheller, Janine. "Modelling excitation coupling in ventricular cardiac myocytes." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19158.

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Um die Kontraktion einer Herzmuskelzelle durch den Kalziumeinstrom zu ermöglichen, ist die Kopplung von Erregung und Kontraktion (ECC) von zentraler Bedeutung. Durch das elektrische Signal einer Nachbarzelle wird die Depolarisation des Sarkolemmas verursacht, wodurch sich die L-Typ-Kalziumkanäale (LKK) öffnen und der Amplifizierungsprozess eingeleitet wird. Letzterer ist bekannt als Kalzium induzierte Kalzium Freisetzung (CICR). Durch die LKK wird ein Kalziumeinstrom in die Zelle ermöglicht, welcher zur Öffnung der Ryanodinrezeptoren (RyR) des Sarkoplasmatischen Retikulums (SR) führt. Durch die Kalziumfreisetzung des SR wird dieses im Cytoplasma akkumuliert. Modelle für diese Prozesse werden seit mehreren Jahrzenten entwickelt. Bisher fehlte jedoch die Kombination aus räumlich aufgelösten Kalziumkonzentrationen der dyadischen Spalte mit stochastischen Simulationen der einzelnen Kalziumkanäle und die Kalziumdynamiken in der ganzen Zelle mit einem Elektrophysiologiemodell einer ganzen Herzmuskelzelle. In dieser Arbeit entwickleten wir ein neues Modell, in welchem die Konzentrationsgradienten von einzelnen Kanälen bis zum Ganzzelllevel räumlich aufgelöst werden. Es wurde der quasistatische Ansatz und die Finite-Elemente-Methode zur Integration partieller Differentialgleichungen verwendet. Es wurden Simulationen mit unterschiedlichen RyR Markow-Kette-Modellen, verschiedenen Parametern für die Bestandteile des SR, verschiedenen Konditionen des Natrium-Kalzium-Austauschers und unter Einbindung der Mitochondrien durchgeführt. Ziel war es, das physiologische Verhalten einer Kaninchen-Herzmuskelzelle zu simulieren. In dem neu entwickelten Multiskalenmodell wurden Hochleistungsrechner verwendet, um detaillierte Informationen über die Verteilung, die Regulation und die Relevanz von den im ECC involvierten Komponenten aufzuzeigen. Zukünftig soll das entwickelte Modell Anwendung bei der Untersuchung von Herzkontraktionen und Herzmuskelversagen finden.
Excitation contraction coupling (ECC) is of central importance to enable the contraction of the cardiac myocyte via calcium in ux. The electrical signal of a neighbouring cell causes the membrane depolarization of the sarcolemma and L-type Ca2+ channels (LCCs) open. The amplifcation process is initiated. This process is known as calcium-induced calcium release (CICR). The calcium in ux through the LCCs activates the ryanodine receptors (RyRs) of the sarcoplasmic reticulum (SR). The Ca2+ release of the SR accumulates calcium in the cytoplasm. For many decades models for these processes were developed. However, previous models have not combined the spatially resolved concentration dynamics of the dyadic cleft including the stochastic simulation of individual calcium channels and the whole cell calcium dynamics with a whole cardiac myocyte electrophysiology model. In this study, we developed a novel approach to resolve concentration gradients from single channel to whole cell level by using quasistatic approximation and finite element method for integrating partial differential equations. We ran a series of simulations with different RyR Markov chain models, different parameters for the SR components, sodium-calcium exchanger conditions, and included mitochondria to approximate physiological behaviour of a rabbit ventricular cardiac myocyte. The new multi-scale simulation tool which we developed makes use of high performance computing to reveal detailed information about the distribution, regulation, and importance of components involved in ECC. This tool will find application in investigation of heart contraction and heart failure.

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13

de, Moissac Danielle. "Structure-function studies of the sodium-calcium exchanger isoforms, NCX1 and NCX2." 2009. http://hdl.handle.net/1993/3158.

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The sodium-calcium exchanger (NCX) is a countertransporter of Na+ and Ca2+ across most cell membranes. It has been identified as an essential component of Ca2+ homeostasis in physiological and disease conditions in both cardiovascular and neurological settings. The exchanger not only transports Na+ and Ca2+, but is also regulated by these ions. Although ionic regulatory profiles differ between NCX isoforms, similar regulatory domains have been identified. Previous structure-function studies have determined key residues within these domains, particularly in the eXchanger Inhibitory Peptide region (XIP) and the Ca2+ binding domains (CBD1/2), which have a direct impact on ionic regulation of the outward exchange currents. Recent structural studies of the Ca2+ binding domains of NCX1 suggest a mechanism by which Ca2+ binding would not only be essential for activation of current but may also influence Na+-dependent inactivation. The alternative splice region is located within the Ca2+ binding domain and may play a role in mediating these regulatory phenotypes. Previous studies have demonstrated that specific combinations of the mutually-exclusive and cassette exons are associated with profound effects on ionic regulation in NCX1. This study focuses on examining the mechanisms by which the alternative splice region, in combination with specific regulatory domains, modulates exchange activity in two isoforms, NCX1 and NCX2. Chimaeric and mutant constructs in the alternative splice region were expressed in Xenopus oocytes and outward Na+-Ca2+ exchange activity was assessed using the giant, excised patch clamp technique. Substitution of the region corresponding to the mutually exclusive exon in either exchanger greatly reduced the extent of Na+-dependent inactivation, independently of intracellular Ca2+ concentrations. However, replacement of both the region corresponding to the mutually exclusive exon A and the XIP region reestablishes a wild-type profile in NCX2. The first mutually exclusive exon is therefore critical in determining Na+ and Ca2+-dependent regulatory properties. Furthermore, non-conserved residues within the XIP region may be essential in maintaining the structural stability of the Na+-dependent inactive state of NCX1, and by interacting with the mutually exclusive exon, may contribute to the structure-function relationship and the distinct regulatory phenotype of each Na+-Ca2+ exchanger variant and isoform.

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Chen, Shao-Hong, and 陳紹弘. "A Study of the Sodium Calcium Ion Exchange Mechanism in NCX." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/06903241036428583046.

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碩士
國立新竹教育大學
應用數學系碩士班
103
Biological sodium calcium ion exchange channel (NCX) removes calcium ions very rapidly from cell inside in exchange with sodium ions from outside. The Poisson-Fermi theory is used to analyze the binding potentials of NCX. It allows us to mathematically investigate the sodium-calcium ion exchange mechanism in NCX. Numerical results have been shown to agree with the experimental results of the sodium-calcium ion exchange.

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15

Schwarz, Erich Marquard. "Calx, A Sodium-Calcium Exchanger of Drosophila melanogaster." Thesis, 1996. https://thesis.library.caltech.edu/11872/12/schwarz-em-1996.pdf.

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Calcium extrusion is necessary for cellular survival and suspected to modulate cellular activity. Drosophila phototransduction is a promising system in which to study calcium export, since it is dominated by calcium activity yet, unlike most calcium-dependent signalling pathways, genetically pliable. The multiple roles of calcium flux in Drosophila phototransduction are reviewed in Chapter One.

Calx, a Drosophila ortholog of mammalian 3Na⁺/1Ca²⁺ exchangers, was isolated and characterized (Chapter Two). Calx's gene product has ~50% identity to its direct mammalian homologs, with more distant similarities to an exchanger-related superfamily. There exist at least seven alternately spliced adult Calx transcripts, with an alternatively spliced miniexon in Calx's protein-coding region. A full-length Calx cDNA of 5408 bp has lengthy, elaborate 5' and 3' UTRs. Calx transcripts are ubiquitously expressed in embryos and adult heads, with one 5.7 kb transcript expressed in photoreceptors; Calx protein is also ubiquitous in adult heads, with a notable presence in photoreceptors and neuropil. Heterologous expression of Calx in Xenopus oocytes shows that it encodes a bona fide sodium-calcium exchanger; unlike mammalian retinal exchangers, it does not depend on potassium for activity. Calx encodes two novel protein motifs, Calx-α and Calx-β. Both are intragenically duplicated, but they probably have different functions: Calx-α is likely to encode residues central to calcium export, while Calx-β may mediate intracellular signalling or cytoskeletal anchoring.

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Yang, Ya-Chi, and 楊雅琪. "Regulation of Sodium-Calcium Exchanger Activity by Creatine Kinase." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/17885972289537598732.

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博士
國立陽明大學
生化暨分子生物研究所
98
Abstract Na+/Ca2+ exchanger (NCX) is one of the major mechanisms for removing Ca2+ from the cytosol especially in cardiac myocytes and neurons, where their physiological activities are triggered by an influx of Ca2+. NCX contains a large intracellular loop (NCXIL) that is responsible for regulating NCX activity. Recent evidence has shown that proteins, including kinases and phosphatases, associate with NCX1IL to form a NCX1 macromolecular complex. To search for the molecules that interact with NCX1IL and regulate NCX1 activity, we used the yeast two-hybrid method to screen a human heart cDNA library and found that the C-terminal region of sarcomeric mitochondrial creatine kinase (sMiCK) interacted with NCX1IL. Moreover, both sMiCK and the muscle-type creatine kinase (CKM) coimmunoprecipitated with NCX1 using lysates of cardiacmyocytes and HEK293T cells that transiently expressed NCX1 and various creatine kinases. Both sMiCK and CKM were able to produce a recovery in the decreased NCX1 activity that was lost under energy-compromised conditions. This regulation is mediated through a putative PKC phosphorylation site of sMiCK and CKM. The autophosphorylation and the catalytic activity of sMiCK and CKM are not required for their regulation of NCX1 activity. Our results suggest a novel mechanism for the regulation of NCX1 activity.

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Chen, Lih-Woan, and 陳麗婉. "Presence of Sodium-Calcium Exchanger in Bovine Chromaffin Cells." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/50026187259025119413.

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碩士
國立陽明大學
生物化學研究所
87
Calcium ion plays important roles in many physiological reactions. It is therefore important to understand how cells regulate their intracellular calcium concentration ([Ca2+ ]i). We have used bovine adrenal chromaffin cells as a model system to study the regulation of [ Ca2+ ]i. Previous results from our laboratory have shown that Na+/Ca2+ exchanger is the major mechanism that is responsible for removing Ca2+ from the cytosol and bringing the [ Ca2+ ]i to the resting level, after the [ Ca2+ ]i is increased by an influx of extracellular Ca2+. There are two major types of Na+-Ca2+ exchanger: NCX (3 Na+: 1 Ca2+) and NCKX (4 Na+: 1 Ca2++1 K+). Preliminary results from our laboratory show that chromaffin cells may contain both NCX and NCKX. In this study, I used Western blot, immunocytochemistry and activity assays to study the types of Na+-Ca2+ exchanger that are present in bovine chromaffin cells. Because of the antibodies used may not recognize the NCX and NCKX in bovine chromaffin cells; no conclusive results were obtained. In the study of Na+/Ca2+ exchange activity, I used the fluorescent indicator, fura-2, to measure the reverse mode of Na+/Ca2+ exchange activity. The chromaffin cells were loaded with Na+ by first treating with carbachol and then transferred to a Na+-free solution to establish a Na+-gradient. The Na+-gradient-dependent Ca2+ increase in the cells was then measured. The results show that there was Na+/Ca2+ exchanger in the chromaffin cells, and the activity was significantly increased in the presence of K+. Therefore, it appears that both NCX and NCKX exist in the chromaffin cells.

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Brittain, Matthew K. "THE ROLE OF THE NMDA RECEPTOR AND REVERSE SODIUM CALCIUM EXCHANGER IN CALCIUM DYSREGULATION IN GLUTAMATE-EXPOSED NEURONS." Thesis, 2012. http://hdl.handle.net/1805/3042.

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Indiana University-Purdue University Indianapolis (IUPUI)
Introduction: During glutamate excitotoxicity, overstimulation of glutamate receptors leads to sustained elevation in cytosolic Ca2+ ([Ca2+]c), or delayed Ca2+ dysregulation (DCD), which is causally linked to cell death. There are two major hypothetical mechanisms for DCD: the continuous activation of N-methyl-D-aspartate-subtype of the ionotropic glutamate receptors (NMDAR) and the reversal of the plasmalemmal Na+/Ca2+ exchanger. However, the contribution of each of these mechanisms in DCD is not completely established. Major results: Neurons exposed to excitotoxic glutamate produced DCD, an increase in cytosolic Na+ ([Na+]c), and plasma membrane depolarization. MK801 and memantine, noncompetitive NMDAR inhibitors, added after glutamate, completely prevented DCD; however AP-5, a competitive NMDAR inhibitor, failed to do so. The NMDAR inhibitors had no effect on lowering elevated [Na+]c or on restoring plasma membrane potential, which are conditions suggesting NCXrev could be involved. In experiments inducing NCXrev, MK801 and memantine completely inhibited Ca2+ dysregulation after glutamate while AP-5 did not. Inhibition of NCXrev, either with KB-R7943 or by preventing the increase in [Na+]c, failed to avert DCD. However, NCXrev inhibition combined with NMDAR blocked by AP-5 completely prevented DCD. Overall, these data suggested that both NMDAR and NCXrev are essential for glutamate-induced DCD, and inhibition of only one mechanism is insufficient to prevent collapse of calcium homeostasis. Based on the data above, we investigated a NMDA receptor antagonist currently in clinical trials for reducing the effects of glutamate excitotoxicity, ifenprodil. Ifenprodil is an activity-dependent, NMDAR inhibitor selective for the NR2B subunit. We found that ifenprodil not only inhibited the NR2B-specific NMDAR, but also inhibited NCXrev. If ifenprodil is combined with PEAQX, a NMDAR inhibitor selective for the NR2A subunit, low concentrations of both inhibitors completely prevent DCD. Conclusion: The inhibition of a single Ca2+ influx mechanism is insufficient in preventing DCD, which requires simultaneous inhibition of both the NMDAR and NCXrev. These findings are critical for the correct interpretation of the experimental results obtained with these inhibitors and for better understanding of their neuroprotective actions.

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19

Xu, Li-Song, and 許立松. "Characteriztation of sodium-calcium exchanger activity in neuroblastoma x glioma hybrid NG108-15 cells." Thesis, 1993. http://ndltd.ncl.edu.tw/handle/63476016161848014396.

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20

Pellman, Jessica J. "Regulation of neuronal calcium homeostasis in Huntington's." Diss., 2015. http://hdl.handle.net/1805/10975.

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Indiana University-Purdue University Indianapolis (IUPUI)
Huntington’s Disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder. There is no cure for HD and the existing therapies only alleviate HD symptoms without eliminating the cause of this neuropathology. HD is linked to a mutation in the huntingtin gene, which results in an elongation of the poly-glutamine stretch in the huntingtin protein (Htt). A major hypothesis is that mutant Htt (mHtt) leads to aberrant Ca2+ homeostasis in affected neurons. This may be caused by increased Ca2+ influx into the cell via the N-methyl-Daspartate (NMDA)-subtype of glutamate receptors. The contribution of two major Ca2+ removal mechanisms, mitochondria and plasmalemmal Na+/Ca2+ exchangers (NCX), in neuronal injury in HD remains unclear. We investigated Ca2+ uptake capacity in isolated synaptic (neuronal) and nonsynaptic mitochondria from the YAC128 mouse model of HD. We found that both Htt and mHtt bind to brain mitochondria and the amount of mitochondriabound mHtt correlates with increased mitochondrial Ca2+ uptake capacity. Mitochondrial Ca2+ accumulation was not impaired in striatal neurons from YAC128 mice. We also found that expression of the NCX1 isoform is increased with age in striatum from YAC128 mice compared to striatum from wild-type mice. Interestingly, mHtt and Htt bind to the NCX3 isoform but not to NCX1. NCX3 expression remains unchanged. To further investigate Ca2+ homeostasis modulation, we examined the role of collapsin response mediator protein 2 (CRMP2) in wild-type neurons. CRMP2 is viewed as an axon guidance protein, but has been found to be involved in Ca2+ signaling. We found that CRMP2 interacts with NMDA receptors (NMDAR) and disrupting this interaction decreases NMDAR activity. CRMP2 also interacts with and regulates NCX3, resulting in NCX3 internalization and decreased activity. Augmented mitochondrial Ca2+ uptake capacity and an increased expression of NCX1 in the presence of mHtt suggest a compensatory reaction in response to increased Ca2+ influx into the cell. The role of NCX warrants further investigation in HD. The novel interactions of CRMP2 with NMDAR and NCX3 provide additional insight into the complexity of Ca2+ homeostasis regulation in neurons and may also be important in HD neuropathology.

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21

Hussain, Munir, and A. Chorvatova. "Effects of caffeine on potassium currents in isolated rat ventricular myocytes." 2009. http://hdl.handle.net/10454/3003.

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No
Rapid exposure of cardiac muscle to high concentrations of caffeine releases Ca 2+ from the sarcoplasmic reticulum (SR). This Ca 2+ is then extruded from the cell by the Na +/Ca 2+ exchanger. Measurement of the current carried by the exchanger ( I Na/Ca) can therefore be used to estimate of the Ca 2+ content of the SR. Previous studies have shown that caffeine, however, can also inhibit K + currents. We therefore investigated whether the inhibitory effects of caffeine on these currents could contaminate measurements of I Na/Ca. Caffeine caused partial inhibition of the inward rectifier K + current ( I K1): the outward current at ¿40 mV was 1.15±0.24 pA/pF in control and decreased to 0.34±0.15 pA/pF in the presence of 10 mmol/l caffeine ( P<0.05, n=15). This was similar to the effect of caffeine on the holding current observed at ¿40 mV in the absence of K + channel block and could therefore account for the contaminating effects of caffeine observed during measurements of I Na/Ca. Moreover, caffeine also partially inhibited the transient outward ( I to) and the delayed rectifier ( I K) K + currents.

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22

Soliman, Daniel. "Ion transport pharmacology in heart disease and type-2 diabetes." Phd thesis, 2010. http://hdl.handle.net/10048/1629.

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The cardiac sodium-calcium exchanger (NCX) is an important membrane protein which regulates cellular calcium necessary for the optimal contractile function of the heart. NCX has become a focal point in ischemic heart disease (IHD) research as evidence suggests that reactive oxygen species (ROS) produced during IHD can cause NCX to malfunction resulting in an intracellular calcium overload leading to cardiac contractile abnormalities. Therefore, I hypothesized that NCX function is mediated by ROS increasing NCX1 activity during cardiac ischemia-reperfusion. To research this hypothesis, I investigated cellular mechanisms which may play a role in NCX dysfunction and also examined methods to correct NCX function. I found that reactive oxygen species directly and irreversibly modify NCX protein, increasing its activity, thereby worsening the calcium overload which is deleterious to cardiac function. I also elucidated the molecular means by which NCX protein modification occurs. Exploring pharmacological means by which to decrease NCX function to relieve the calcium overload and reduce the damage to the heart, I discovered that ranolazine (Ranexa), indicated for the treatment of angina pectoris inhibits NCX activity directly, thereby further reducing the calcium overload-induced injury to the heart. Furthermore, many IHD patients are also co-morbid for type-2 diabetes. These patients are prescribed sulfonylurea (SU) agents which act at the ATP sensitive K+ channel (KATP). One agent such as glibenclamide is known to have cardiotoxic side effects. Therefore, SUs devoid of any cardiac side effects would beneficial. Interestingly, patients possessing the genetic variant E23K-S1369A KATP channel have improved blood glucose levels with the use of the SU gliclazide. Therefore, I determined the functional mechanism by which gliclazide has increased inhibition at the KATP channel. These findings have implications for type-2 diabetes therapy, in which 20% of the type-2 diabetic population carries the KATP channel variant. In summary, the findings presented in this thesis have implications on treatment strategies in the clinical setting, as a NCX inhibitor can be beneficial in IHD and possibly type-2 diabetes. Moreover, a pharmacogenomic approach in treating type-2 diabetes may also provide a positive outcome when considering co-morbid cardiac complications such as atrial fibrillation and heart failure.

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23

Bellmann, Sarah. "Die Bedeutung der Ca2+/Calmodulin-abhängigen Proteinkinase IIδ für die zytosolische Natrium- und Kalziumüberladung sowie Arrhythmogenese in Herzmuskelzellen." Doctoral thesis, 2013. http://hdl.handle.net/11858/00-1735-0000-000D-F0E3-D.

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Dissertations / Theses on the topic 'Sodium/calcium exchanger (NCX)'

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