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1
Chovancova, Barbora, Veronika Liskova, Petr Babula, and Olga Krizanova. "Role of Sodium/Calcium Exchangers in Tumors." Biomolecules 10, no. 9 (August 31, 2020): 1257. http://dx.doi.org/10.3390/biom10091257.
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The sodium/calcium exchanger (NCX) is a unique calcium transport system, generally transporting calcium ions out of the cell in exchange for sodium ions. Nevertheless, under special conditions this transporter can also work in a reverse mode, in which direction of the ion transport is inverted—calcium ions are transported inside the cell and sodium ions are transported out of the cell. To date, three isoforms of the NCX have been identified and characterized in humans. Majority of information about the NCX function comes from isoform 1 (NCX1). Although knowledge about NCX function has evolved rapidly in recent years, little is known about these transport systems in cancer cells. This review aims to summarize current knowledge about NCX functions in individual types of cancer cells.
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Roome, Chris J., Emmet M. Power, and Ruth M. Empson. "Transient reversal of the sodium/calcium exchanger boosts presynaptic calcium and synaptic transmission at a cerebellar synapse." Journal of Neurophysiology 109, no. 6 (March 15, 2013): 1669–80. http://dx.doi.org/10.1152/jn.00854.2012.
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The sodium/calcium exchanger (NCX) is a widespread transporter that exchanges sodium and calcium ions across excitable membranes. Normally, NCX mainly operates in its “forward” mode, harnessing the electrochemical gradient of sodium ions to expel calcium. During membrane depolarization or elevated internal sodium levels, NCX can instead switch the direction of net flux to expel sodium and allow calcium entry. Such “reverse”-mode NCX operation is frequently implicated during pathological or artificially extended periods of depolarization, not during normal activity. We have used fast calcium imaging, mathematical simulation, and whole cell electrophysiology to study the role of NCX at the parallel fiber-to-Purkinje neuron synapse in the mouse cerebellum. We show that nontraditional, reverse-mode NCX activity boosts the amplitude and duration of parallel fiber calcium transients during short bursts of high-frequency action potentials typical of their behavior in vivo. Simulations, supported by experimental manipulations, showed that accumulation of intracellular sodium drove NCX into reverse mode. This mechanism fueled additional calcium influx into the parallel fibers that promoted synaptic transmission to Purkinje neurons for up to 400 ms after the burst. Thus we provide the first functional demonstration of transient and fast NCX-mediated calcium entry at a major central synapse. This unexpected contribution from reverse-mode NCX appears critical for shaping presynaptic calcium dynamics and transiently boosting synaptic transmission, and is likely to optimize the accuracy of cerebellar information transfer.
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Smith, L., and J. B. Smith. "Activation of adenylyl cyclase downregulates sodium/calcium exchanger of arterial myocytes." American Journal of Physiology-Cell Physiology 269, no. 6 (December 1, 1995): C1379—C1384. http://dx.doi.org/10.1152/ajpcell.1995.269.6.c1379.
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Chronic elevation of adenosine 3',5'-cyclic monophosphate (cAMP) is known to inhibit the proliferation of cultured vascular smooth muscle cells. The present findings show that the activation of adenylyl cyclase with forskolin decreased Na+/Ca2+ exchanger (NCX) mRNA and activity. Fetal bovine serum restored NCX transcript and activity. The changes in NCX transcript preceded the changes in NCX activity. Incubation of low-passage immortalized myocytes with forskolin plus 3-isobutyl-1-methylxanthine (IBMX), which inhibits cAMP phosphodiesterase, decreased NCX mRNA by 60% in 6 h and 80% in 24 h. After a 6-h lag, forskolin plus IBMX decreased NCX activity almost linearly to 20% of control at 40 h. 1,9-Dideoxyforskolin, which does not activate adenylyl cyclase, had no effect on NCX mRNA or activity. Forskolin plus IBMX decreased the c-Myc transcript, an immediate-early gene whose expression correlates with cell proliferation, but had no effect on plasma membrane Ca(2+)-ATPase transcripts. Removal of forskolin plus IBMX and addition of fetal bovine serum increased NCX and c-Myc transcripts seven- to eightfold in 6 h and restored NCX activity in 24 h. Inhibition of protein or RNA synthesis by cycloheximide or actinomycin D, respectively, prevented the increase in NCX mRNA. In contrast to blocking NCX induction, cycloheximide potentiated c-Myc induction by serum. Transcription factors that regulate myocyte growth may mediate the opposing influences of serum and forskolin on NCX mRNA and activity.
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Chernysh, Olga, Madalina Condrescu, and John P. Reeves. "Sodium-dependent inactivation of sodium/calcium exchange in transfected Chinese hamster ovary cells." American Journal of Physiology-Cell Physiology 295, no. 4 (October 2008): C872—C882. http://dx.doi.org/10.1152/ajpcell.00221.2008.
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High concentrations of cytosolic Na+ ions induce the time-dependent formation of an inactive state of the Na+/Ca2+ exchanger (NCX), a process known as Na+-dependent inactivation. NCX activity was measured as Ca2+ uptake in fura 2-loaded Chinese hamster ovary (CHO) cells expressing the wild-type (WT) NCX or mutants that are hypersensitive (F223E) or resistant (K229Q) to Na+-dependent inactivation. As expected, 1) Na+-dependent inactivation was promoted by high cytosolic Na+ concentration, 2) the F223E mutant was more susceptible than the WT exchanger to inactivation, whereas the K229Q mutant was resistant, and 3) inactivation was enhanced by cytosolic acidification. However, in contrast to expectations from excised patch studies, 1) the WT exchanger was resistant to Na+-dependent inactivation unless cytosolic pH was reduced, 2) reducing cellular phosphatidylinositol-4,5-bisphosphate levels did not induce Na+-dependent inactivation in the WT exchanger, 3) Na+-dependent inactivation did not increase the half-maximal cytosolic Ca2+ concentration for allosteric Ca2+ activation, 4) Na+-dependent inactivation was not reversed by high cytosolic Ca2+ concentrations, and 5) Na+-dependent inactivation was partially, but transiently, reversed by an increase in extracellular Ca2+ concentration. Thus Na+-dependent inactivation of NCX expressed in CHO cells differs in several respects from the inactivation process measured in excised patches. The refractoriness of the WT exchanger to Na+-dependent inactivation suggests that this type of inactivation is unlikely to be a strong regulator of exchange activity under physiological conditions but would probably act to inhibit NCX-mediated Ca2+ influx during ischemia.
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Münch, Götz, Kai Rosport, Christine Baumgartner, Zhongmin Li, Silvia Wagner, Andreas Bültmann, and Martin Ungerer. "Functional alterations after cardiac sodium-calcium exchanger overexpression in heart failure." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 2 (August 2006): H488—H495. http://dx.doi.org/10.1152/ajpheart.01324.2005.
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The sodium-calcium exchanger (NCX) is discussed as one of the key proteins involved in heart failure. However, the causal role and the extent to which NCX contributes to contractile dysfunction during heart failure are poorly understood. NCX overexpression was induced by infection with an adenovirus coding for NCX, which coexpressed green fluorescence protein (GFP) (AdNCX) by ex vivo gene transfer to nonfailing and failing rabbit cardiomyocytes. Myocardial gene transfer in rabbits in vivo was achieved by adenoviral delivery via aortic cross-clamping. Peak cell shortening of cardiomyocytes was determined photo-optically. Hemodynamic parameters in vivo were determined by echocardiography (fractional shortening) and tip catheter [maximal first derivative of left ventricular (LV) pressure (dP/d tmax); maximal negative derivative of LV pressure (−dP/d tmax)]. Peak cell shortening was depressed after NCX gene delivery in isolated nonfailing and in failing cardiomyocytes. In nonfailing rabbits in vivo, basal systolic contractility (fractional shortening and dP/d tmax) and maximum rate of LV relaxation (−dP/d tmax) in vivo were largely unaffected after NCX overexpression. However, during heart failure, long-term NCX overexpression over 2 wk significantly improved fractional shortening and dP/d tmax compared with AdGFP-infected rabbits, both without inotropic stimulation and after β-adrenergic stimulation with isoproterenol. −dP/d tmax was also improved after NCX overexpression in the failing rabbits group. These results indicate that short-term effects of NCX overexpression impair contractility of isolated failing and nonfailing rabbit cardiomyocytes. NCX overexpression over 2 wk in vivo does not seem to affect myocardial contractility in nonfailing rabbits. Interestingly, in vivo overexpression of NCX decreased the progression of systolic and diastolic contractile dysfunction and improved β-adrenoceptor-mediated contractile reserve in heart failure in rabbits in vivo.
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Torrente, Angelo G., Rui Zhang, Audrey Zaini, Jorge F. Giani, Jeanney Kang, Scott T. Lamp, Kenneth D. Philipson, and Joshua I. Goldhaber. "Burst pacemaker activity of the sinoatrial node in sodium–calcium exchanger knockout mice." Proceedings of the National Academy of Sciences 112, no. 31 (July 20, 2015): 9769–74. http://dx.doi.org/10.1073/pnas.1505670112.
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In sinoatrial node (SAN) cells, electrogenic sodium–calcium exchange (NCX) is the dominant calcium (Ca) efflux mechanism. However, the role of NCX in the generation of SAN automaticity is controversial. To investigate the contribution of NCX to pacemaking in the SAN, we performed optical voltage mapping and high-speed 2D laser scanning confocal microscopy (LSCM) of Ca dynamics in an ex vivo intact SAN/atrial tissue preparation from atrial-specific NCX knockout (KO) mice. These mice lack P waves on electrocardiograms, and isolated NCX KO SAN cells are quiescent. Voltage mapping revealed disorganized and arrhythmic depolarizations within the NCX KO SAN that failed to propagate into the atria. LSCM revealed intermittent bursts of Ca transients. Bursts were accompanied by rising diastolic Ca, culminating in long pauses dominated by Ca waves. The L-type Ca channel agonist BayK8644 reduced the rate of Ca transients and inhibited burst generation in the NCX KO SAN whereas the Ca buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetoxymethyl ester) (BAPTA AM) did the opposite. These results suggest that cellular Ca accumulation hinders spontaneous depolarization in the NCX KO SAN, possibly by inhibiting L-type Ca currents. The funny current (If) blocker ivabradine also suppressed NCX KO SAN automaticity. We conclude that pacemaker activity is present in the NCX KO SAN, generated by a mechanism that depends upon If. However, the absence of NCX-mediated depolarization in combination with impaired Ca efflux results in intermittent bursts of pacemaker activity, reminiscent of human sinus node dysfunction and “tachy-brady” syndrome.
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de Ruijter, Wouter, Ger J. M. Stienen, Jan van Klarenbosch, and Jacob J. de Lange. "Negative and Positive Inotropic Effects of Propofol via L-type Calcium Channels and the Sodium-Calcium Exchanger in Rat Cardiac Trabeculae." Anesthesiology 97, no. 5 (November 1, 2002): 1146–55. http://dx.doi.org/10.1097/00000542-200211000-00019.
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Background Conflicting opinions are present in the literature regarding the origin of the negative inotropic effect of propofol on the myocardium. This study aims to resolve these discrepancies by investigating the inotropic effects of propofol the L-type calcium channels and the sodium-calcium exchanger (NCX). Methods The effect of 20 microg/ml propofol on force development was determined in rat cardiac trabeculae at different pacing frequencies and different extracellular calcium concentrations. Postrest potentiation, sodium withdrawal during quiescence, and the NCX inhibitor KB-R7943 were used to study changes in the activity of the reverse mode of the NCX by propofol. Results The effect of propofol on steady state peak force depended on pacing frequency and calcium concentration. A negative inotropic effect was observed at pacing frequencies greater than 0.5 Hz, but a positive inotropic effect was observed at 0.1 Hz and low calcium, which cannot be explained by an effect on the L-type calcium channel. Propofol enhanced postrest potentiation in a calcium-dependent manner. Sodium withdrawal during quiescence and the use of the specific NCX inhibitor KB-R7943 provided evidence for an enhancement of calcium influx by propofol the reverse mode of the NCX. Conclusions The effects of propofol on the myocardium depend on pacing frequency and calcium concentration. The positive inotropic effect of propofol is associated with increased calcium influx the reverse mode of the NCX. The authors conclude that the net inotropic effect of propofol is the result of its counteracting influence on the functioning of the L-type calcium channel and the NCX.
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Padín, Juan-Fernando, José-Carlos Fernández-Morales, Román Olivares, Stefan Vestring, Juan-Alberto Arranz-Tagarro, Enrique Calvo-Gallardo, Ricardo de Pascual, Luís Gandía, and Antonio G. García. "Plasmalemmal sodium-calcium exchanger shapes the calcium and exocytotic signals of chromaffin cells at physiological temperature." American Journal of Physiology-Cell Physiology 305, no. 2 (July 15, 2013): C160—C172. http://dx.doi.org/10.1152/ajpcell.00016.2013.
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The activity of the plasmalemmal Na+/Ca2+ exchanger (NCX) is highly sensitive to temperature. We took advantage of this fact to explore here the effects of the NCX blocker KB-R7943 (KBR) at 22 and 37°C on the kinetics of Ca2+ currents ( ICa), cytosolic Ca2+ ([Ca2+]c) transients, and catecholamine release from bovine chromaffin cells (BCCs) stimulated with high K+, caffeine, or histamine. At 22°C, the effects of KBR on those parameters were meager or nil. However, at 37°C whereby the NCX is moving Ca2+ at a rate fivefold higher than at 22°C, various of the effects of KBR were pronounced, namely: 1) no effects on ICa; 2) reduction of the [Ca2+]c transient amplitude and slowing down of its rate of clearance; 3) blockade of the K+-elicited quantal release of catecholamine; 4) blockade of burst catecholamine release elicited by K+; 5) no effect on catecholamine release elicited by short K+ pulses (1–2 s) and blockade of the responses produced by longer K+ pulses (3–5 s); and 6) potentiation of secretion elicited by histamine or caffeine. Furthermore, the more selective NCX blocker SEA0400 also potentiated the secretory responses to caffeine. The results suggest that at physiological temperature the NCX substantially contributes to shaping the kinetics of [Ca2+]c transients and the exocytotic responses elicited by Ca2+ entry through Ca2+ channels as well as by Ca2+ release from the endoplasmic reticulum.
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Haug-Collet, K., B. Pearson, R. Webel, R. T. Szerencsei, R. J. Winkfein, P. P. M. Schnetkamp, and N. J. Colley. "Cloning and Characterization of a Potassium-Dependent Sodium/Calcium Exchanger in Drosophila." Journal of Cell Biology 147, no. 3 (November 1, 1999): 659–70. http://dx.doi.org/10.1083/jcb.147.3.659.
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Sodium/calcium(-potassium) exchangers (NCX and NCKX) are critical for the rapid extrusion of calcium, which follows the stimulation of a variety of excitable cells. To further understand the mechanisms of calcium regulation in signaling, we have cloned a Drosophila sodium/calcium-potassium exchanger, Nckx30C. The overall deduced protein topology for NCKX30C is similar to that of mammalian NCKX, having five membrane-spanning domains in the NH2 terminus separated from six at the COOH-terminal end by a large intracellular loop. We show that NCKX30C functions as a potassium-dependent sodium/calcium exchanger, and is not only expressed in adult neurons as was expected, but is also expressed during ventral nerve cord development in the embryo and in larval imaginal discs. Nckx30C is expressed in a dorsal–ventral pattern in the eye-antennal disc in a pattern that is similar to, but broader than that of wingless, suggesting that large fluxes of calcium may be occurring during imaginal disc development. Nckx30C may not only function in the removal of calcium and maintenance of calcium homeostasis during signaling in the adult, but may also play a critical role in signaling during development.
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Li, Sen, Anant Chopra, Wendy Keung, Camie W. Y. Chan, Kevin D. Costa, Chi-Wing Kong, Roger J. Hajjar, Christopher S. Chen, and Ronald A. Li. "Sarco/endoplasmic reticulum Ca2+-ATPase is a more effective calcium remover than sodium-calcium exchanger in human embryonic stem cell-derived cardiomyocytes." American Journal of Physiology-Heart and Circulatory Physiology 317, no. 5 (November 1, 2019): H1105—H1115. http://dx.doi.org/10.1152/ajpheart.00540.2018.
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Human pluripotent stem cell (hPSCs)-derived ventricular (V) cardiomyocytes (CMs) display immature Ca2+–handing properties with smaller transient amplitudes and slower kinetics due to such differences in crucial Ca2+-handling proteins as the poor sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump but robust Na+-Ca2+ exchanger (NCX) activities in human embryonic stem cell (ESC)-derived VCMs compared with adult. Despite their fundamental importance in excitation-contraction coupling, the relative contribution of SERCA and NCX to Ca2+-handling of hPSC-VCMs remains unexplored. We systematically altered the activities of SERCA and NCX in human embryonic stem cell-derived ventricular cardiomyocytes (hESC-VCMs) and their engineered microtissues, followed by examining the resultant phenotypic consequences. SERCA overexpression in hESC-VCMs shortened the decay of Ca2+ transient at low frequencies (0.5 Hz) without affecting the amplitude, SR Ca2+ content and Ca2+ baseline. Interestingly, short hairpin RNA-based NCX suppression did not prolong the transient decay, indicating a compensatory response for Ca2+ removal. Although hESC-VCMs and their derived microtissues exhibited negative frequency-transient/force responses, SERCA overexpression rendered them less negative at high frequencies (>2 Hz) by accelerating Ca2+ sequestration. We conclude that for hESC-VCMs and their microtissues, SERCA, rather than NCX, is the main Ca2+ remover during diastole; poor SERCA expression is the leading cause for immature negative-frequency/force responses, which can be partially reverted by forced expression. Combinatorial approach to mature calcium handling in hESC-VCMs may help shed further mechanistic insights. NEW & NOTEWORTHY In this study of human pluripotent stem cell-derived cardiomyocytes, we studied the role of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and Na+-Ca2+ exchanger (NCX) in Ca2+ handling. Our data support the notion that SERCA is more effective in cytosolic calcium removal than the NCX.
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Linask, Kersti K., Ming-Da Han, Michael Artman, and Cheryl A. Ludwig. "Sodium-calcium exchanger (NCX-1) and calcium modulation: NCX protein expression patterns and regulation of early heart development." Developmental Dynamics 221, no. 3 (2001): 249–64. http://dx.doi.org/10.1002/dvdy.1131.
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Loffing, Johannes, Dominique Loffing-Cueni, Victor Valderrabano, Lea Kläusli, Steven C. Hebert, Bernard C. Rossier, Joost G. J. Hoenderop, René J. M. Bindels, and Brigitte Kaissling. "Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron." American Journal of Physiology-Renal Physiology 281, no. 6 (December 1, 2001): F1021—F1027. http://dx.doi.org/10.1152/ajprenal.0085.2001.
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First published August 15, 2001; 10.1152/ajprenal. 00085.2001.—The organization of Na+ and Ca2+ transport pathways along the mouse distal nephron is incompletely known. We revealed by immunohistochemistry a set of Ca2+ and Na+transport proteins along the mouse distal convolution. The thiazide-sensitive Na+-Cl− cotransporter (NCC) characterized the distal convoluted tubule (DCT). The amiloride-sensitive epithelial Na+ channel (ENaC) colocalized with NCC in late DCT (DCT2) and extended to the downstream connecting tubule (CNT) and collecting duct (CD). In early DCT (DCT1), the basolateral Ca2+-extruding proteins [Na+/Ca2+ exchanger (NCX), plasma membrane Ca2+-ATPase (PCMA)] and the cytoplasmic Ca2+-binding protein calbindin D28K (CB) were found at very low levels, whereas the cytoplasmic Ca2+/Mg2+-binding protein parvalbumin was highly abundant. NCX, PMCA, and CB prevailed in DCT2 and CNT, where we located the apical epithelial Ca2+ channel (ECaC1). Its subcellular localization changed from apical in DCT2 to exclusively cytoplasmic at the end of CNT. NCX and PMCA decreased in parallel with the fading of ECaC1 in the apical membrane. All three of them were undetectable in CD. These findings disclose DCT2 and CNT as major sites for transcellular Ca2+ transport in the mouse distal nephron. Cellular colocalization of Ca2+ and Na+ transport pathways suggests their mutual interactions in transport regulation.
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Jha, Brajesh Kumar, and Amrita Jha. "Two dimensional finite element estimation of calcium ions in presence fo NCX and Buffers in Astrocytes." Boletim da Sociedade Paranaense de Matemática 36, no. 1 (January 1, 2018): 151. http://dx.doi.org/10.5269/bspm.v36i1.29137.
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Sodium calcium exchanger (NCX) plays effective role in signal transduction in most of the nerve cells like neuron, astrocytes. Sodium ion affects the cytosolic calcium concentration label in Astrocytes via various channels. This affects the movement of the nerve impulse from one cell to other cell. In this paper two dimensional model is developedin the form of diffusion equation to study the effect of NCX in presence and negligence of buffer in Astrocytes. Finite element method is employed to solve the problem and simulated in Matlab to estimate the affect of various parameter like flux, diffusion coefficient, buffer concentration, etc.
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Shiraga, Masamichi, Yoshiaki Tomiyama, Shigenori Honda, Hidenori Suzuki, Satoru Kosugi, Seiji Tadokoro, Yuzuru Kanakura, Kenjiro Tanoue, Yoshiyuki Kurata, and Yuji Matsuzawa. "Involvement of Na+/Ca2+ Exchanger in Inside-Out Signaling Through the Platelet Integrin IIbβ3." Blood 92, no. 10 (November 15, 1998): 3710–20. http://dx.doi.org/10.1182/blood.v92.10.3710.
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Abstract The platelet integrin IIbβ3 has become a new target for the treatment of pathological thrombosis. It becomes apparent that the affinity of IIbβ3 for its ligands is dynamically regulated by inside-out signaling. However, the components that couple diverse intracellular signals to the cytoplasmic domains of IIbβ3 remain obscure. Employing a chymotrypsin-induced IIbβ3 activation model, we previously proposed the hypothesis that Na+/Ca2 +exchanger (NCX) may be involved in inside-out signaling (Shiraga et al:Blood 88:2594, 1996). In the present study, employing two unrelated Na+/Ca2+ exchange inhibitors, 3′,4′-dichlorobenzamil (DCB) and bepridil, we investigated the role of NCX in platelet activation induced by various agonists in detail. Both inhibitors abolished platelet aggregation induced by all agonists examined via the inhibition of IIbβ3 activation. Moreover, these inhibitors abolished IIbβ3 activation induced by phorbol 12-myristate 13-acetate or A23187. On the other hand, neither of these inhibitors showed apparent inhibitory effects on protein phosphorylation of pleckstrin or myosin light chain, or an increase in intracellular calcium ion concentrations evoked by 0.1 U/mL thrombin. These effects of the NCX inhibitors are in striking contrast to those of protein kinase C inhibitor, Ro31-8220. Biochemical and ultrastructural analyses showed that NCX inhibitors, particularly DCB, made platelets “thrombasthenic”. These findings suggest that the NCX is involved in the common steps of inside-out signaling through integrin IIbβ3.
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Shiraga, Masamichi, Yoshiaki Tomiyama, Shigenori Honda, Hidenori Suzuki, Satoru Kosugi, Seiji Tadokoro, Yuzuru Kanakura, Kenjiro Tanoue, Yoshiyuki Kurata, and Yuji Matsuzawa. "Involvement of Na+/Ca2+ Exchanger in Inside-Out Signaling Through the Platelet Integrin IIbβ3." Blood 92, no. 10 (November 15, 1998): 3710–20. http://dx.doi.org/10.1182/blood.v92.10.3710.422k13_3710_3720.
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The platelet integrin IIbβ3 has become a new target for the treatment of pathological thrombosis. It becomes apparent that the affinity of IIbβ3 for its ligands is dynamically regulated by inside-out signaling. However, the components that couple diverse intracellular signals to the cytoplasmic domains of IIbβ3 remain obscure. Employing a chymotrypsin-induced IIbβ3 activation model, we previously proposed the hypothesis that Na+/Ca2 +exchanger (NCX) may be involved in inside-out signaling (Shiraga et al:Blood 88:2594, 1996). In the present study, employing two unrelated Na+/Ca2+ exchange inhibitors, 3′,4′-dichlorobenzamil (DCB) and bepridil, we investigated the role of NCX in platelet activation induced by various agonists in detail. Both inhibitors abolished platelet aggregation induced by all agonists examined via the inhibition of IIbβ3 activation. Moreover, these inhibitors abolished IIbβ3 activation induced by phorbol 12-myristate 13-acetate or A23187. On the other hand, neither of these inhibitors showed apparent inhibitory effects on protein phosphorylation of pleckstrin or myosin light chain, or an increase in intracellular calcium ion concentrations evoked by 0.1 U/mL thrombin. These effects of the NCX inhibitors are in striking contrast to those of protein kinase C inhibitor, Ro31-8220. Biochemical and ultrastructural analyses showed that NCX inhibitors, particularly DCB, made platelets “thrombasthenic”. These findings suggest that the NCX is involved in the common steps of inside-out signaling through integrin IIbβ3.
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Galli, Gina L. J., Edwin W. Taylor, and Holly A. Shiels. "Calcium flux in turtle ventricular myocytes." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 6 (December 2006): R1781—R1789. http://dx.doi.org/10.1152/ajpregu.00421.2006.
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The relative contribution of the sarcoplasmic reticulum (SR), the L-type Ca2+ channel and the Na+/Ca2+ exchanger (NCX) were assessed in turtle ventricular myocytes using epifluorescent microscopy and electrophysiology. Confocal microscopy images of turtle myocytes revealed spindle-shaped cells, which lacked T-tubules and had a large surface area-to-volume ratio. Myocytes loaded with the fluorescent Ca2+-sensitive dye Fura-2 elicited Ca2+ transients, which were insensitive to ryanodine and thapsigargin, indicating the SR plays a small role in the regulation of contraction and relaxation in the turtle ventricle. Sarcolemmal Ca2+ currents were measured using the perforated-patch voltage-clamp technique. Depolarizing voltage steps to 0 mV elicited an inward current that could be blocked by nifedipine, indicating the presence of Ca2+ currents originating from L-type Ca2+ channels (ICa). The density of ICa was 3.2 ± 0.5 pA/pF, which led to an overall total Ca2+ influx of 64.1 ± 9.3 μM/l. NCX activity was measured as the Ni+-sensitive current at two concentrations of intracellular Na+ (7 and 14 mM). Total Ca2+ influx through the NCX during depolarizing voltage steps to 0 mV was 58.5 ± 7.7 μmol/l and 26.7 ± 3.2 μmol/l at 14 and 7 mM intracellular Na+, respectively. In the absence of the SR and L-type Ca2+ channels, the NCX is able to support myocyte contraction independently. Our results indicate turtle ventricular myocytes are primed for sarcolemmal Ca2+ transport, and most of the Ca2+ used for contraction originates from the L-type Ca2+ channel.
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Polo-Parada, Luis, and Amol A. Modgi. "Differences in Expression and Function in the Atrium versus Ventricle of the Sodium-Calcium Exchanger in the Embryonic Chicken Heart." ISRN Physiology 2013 (September 1, 2013): 1–12. http://dx.doi.org/10.1155/2013/921527.
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Heart function is well known to be dependent on intrinsic electrical activity. This electrical activity is primarily mediated by a combination of interactions among various ionic channels and transporters. In this study, we demonstrate that the Na+-Ca2+ exchanger (NCX) is equally present in both atrial and ventricular cells at early stages of development (st. 13). However, ventricular cells exhibit an increase in NCX messenger ribonucleic acid (mRNA) levels during later stages of development, while levels in atrial cells remain constant. We demonstrate that the current density of the NCX increases with development in the ventricle but remains constant in the atrial cells. Furthermore we demonstrate that the NCX has a major role in shaping the cardiac action potential at early stages mainly in ventricular cells (st. 14) than later mainly in the atrial cells (st. 30).
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Pittner, János, Kristie Rhinehart, and Thomas L. Pallone. "Ouabain modulation of endothelial calcium signaling in descending vasa recta." American Journal of Physiology-Renal Physiology 291, no. 4 (October 2006): F761—F769. http://dx.doi.org/10.1152/ajprenal.00326.2005.
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Using fura 2-loaded vessels, we tested whether ouabain modulates endothelial cytoplasmic calcium concentration ([Ca2+]CYT) in rat descending vasa recta (DVR). Over a broad range between 10−10 and 10−4 M, ouabain elicited biphasic peak and plateau [Ca2+]CYT elevations. Blockade of voltage-gated Ca2+ entry with nifedipine did not affect the response to ouabain mitigating against a role for myo-endothelial gap junctions. Reduction of extracellular Na+ concentration ([Na+]o) or Na+/Ca2+ exchanger (NCX) inhibition with SEA-0400 (10−6 M) elevated [Ca2+]CYT, supporting a role for NCX in the setting of basal [Ca2+]CYT. SEA-0400 abolished the [Ca2+]CYT response to ouabain implicating NCX as a mediator. The transient peak phase of [Ca2+]CYT elevation that followed either ouabain or reduction of [Na+]o was abolished by 2-aminoethoxydiphenyl borate (5 × 10−5 M). Cation channel blockade with La3+ (10 μM) or SKF-96365 (10 μM) also attenuated the ouabain-induced [Ca2+]CYT response. Ouabain pretreatment increased the [Ca2+]CYT elevation elicited by bradykinin (10−7 M). We conclude that inhibition of ouabain-sensitive Na+-K+-ATPase enhances DVR endothelial Ca2+ store loading and modulates [Ca2+]CYT signaling through mechanisms that involve NCX, Ca2+ release, and cation channel activation.
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Kurnellas, M. P., K. C. Donahue, and S. Elkabes. "Mechanisms of neuronal damage in multiple sclerosis and its animal models: role of calcium pumps and exchangers." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 923–26. http://dx.doi.org/10.1042/bst0350923.
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Multiple sclerosis is an inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Increasing evidence indicates that neuronal pathology and axonal injury are early hallmarks of multiple sclerosis and are major contributors to progressive and permanent disability. Yet, the mechanisms underlying neuronal dysfunction and damage are not well defined. Elucidation of such mechanisms is of critical importance for the development of therapeutic strategies that will prevent neurodegeneration and confer neuroprotection. PMCA2 (plasma-membrane Ca2+-ATPase 2) and the NCX (Na+/Ca2+ exchanger) have been implicated in impairment of axonal and neuronal function in multiple sclerosis and its animal models. As PMCA2 and NCX play critical roles in calcium extrusion in cells, alterations in their expression or activity may affect calcium homoeostasis and thereby induce intracellular injury mechanisms. Interventions that restore normal PMCA2 and NCX activity may prevent or slow disease progression by averting neurodegeneration.
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Giladi, Moshe, Reut Shor, Michal Lisnyansky, and Daniel Khananshvili. "Structure-Functional Basis of Ion Transport in Sodium–Calcium Exchanger (NCX) Proteins." International Journal of Molecular Sciences 17, no. 11 (November 22, 2016): 1949. http://dx.doi.org/10.3390/ijms17111949.
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Kang, Beom Seok, Bo Young Choi, A. Ra Kho, Song Hee Lee, Dae Ki Hong, Jeong Hyun Jeong, Dong Hyeon Kang, Min Kyu Park, and Sang Won Suh. "An Inhibitor of the Sodium–Hydrogen Exchanger-1 (NHE-1), Amiloride, Reduced Zinc Accumulation and Hippocampal Neuronal Death after Ischemia." International Journal of Molecular Sciences 21, no. 12 (June 14, 2020): 4232. http://dx.doi.org/10.3390/ijms21124232.
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Acidosis in the brain plays an important role in neuronal injury and is a common feature of several neurological diseases. It has been reported that the sodium–hydrogen exchanger-1 (NHE-1) is a key mediator of acidosis-induced neuronal injury. It modulates the concentration of intra- and extra-cellular sodium and hydrogen ions. During the ischemic state, excessive sodium ions enter neurons and inappropriately activate the sodium–calcium exchanger (NCX). Zinc can also enter neurons through voltage-gated calcium channels and NCX. Here, we tested the hypothesis that zinc enters the intracellular space through NCX and the subsequent zinc accumulation induces neuronal cell death after global cerebral ischemia (GCI). Thus, we conducted the present study to confirm whether inhibition of NHE-1 by amiloride attenuates zinc accumulation and subsequent hippocampus neuronal death following GCI. Mice were subjected to GCI by bilateral common carotid artery (BCCA) occlusion for 30 min, followed by restoration of blood flow and resuscitation. Amiloride (10 mg/kg, intraperitoneally (i.p.)) was immediately injected, which reduced zinc accumulation and neuronal death after GCI. Therefore, the present study demonstrates that amiloride attenuates GCI-induced neuronal injury, likely via the prevention of intracellular zinc accumulation. Consequently, we suggest that amiloride may have a high therapeutic potential for the prevention of GCI-induced neuronal death.
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Boscia, Francesca, Rosaria Gala, Giuseppe Pignataro, Andrea de Bartolomeis, Maria Cicale, Alberto Ambesi-Impiombato, Gianfranco Di Renzo, and Lucio Annunziato. "Permanent Focal Brain Ischemia Induces Isoform-Dependent Changes in the Pattern of Na+/Ca2+ Exchanger Gene Expression in the Ischemic Core, Periinfarct Area, and Intact Brain Regions." Journal of Cerebral Blood Flow & Metabolism 26, no. 4 (August 17, 2005): 502–17. http://dx.doi.org/10.1038/sj.jcbfm.9600207.
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Dysregulation of sodium [Na+]i and calcium [Ca2+]i homeostasis plays a pivotal role in the pathophysiology of cerebral ischemia. Three gene products of the sodium–calcium exchanger family NCX1, NCX2, and NCX3 couple, in a bidirectional way, the movement of these ions across the cell membrane during cerebral ischemia. Each isoform displays a selective distribution in the rat brain. To determine whether NCX gene expression can be regulated after cerebral ischemia, we used NCX isoform-specific antisense radiolabeled probes to analyze, by radioactive in situ hybridization histochemistry, the pattern of NCX1, NCX2, and NCX3 transcripts in the ischemic core, periinfarct area, as well as in nonischemic brain regions, after 6 and 24 h of permanent middle cerebral artery occlusion (pMCAO) in rats. We found that in the focal region, comprising divisions of the prefrontal, somatosensory, and insular cortices, all three NCX transcripts were downregulated. In the periinfarct area, comprising part of the motor cortex and the lateral compartments of the caudate-putamen, NCX2 messenger ribonucleic acid (mRNA) was downregulated, whereas NCX3 mRNA was significantly upregulated. In remote nonischemic brain regions such as the prelimbic and infralimbic cortices, and tenia tecta, both NCX1 and NCX3 transcripts were upregulated, whereas in the medial caudate-putamen only NCX3 transcripts increased. In all these intact regions, NCX2 signal strongly decreased. These results indicate that NCX gene expression is regulated after pMCAO in a differential manner, depending on the exchanger isoform and region involved in the insult. These data may provide a better understanding of each NCX subtype's pathophysiologic role and may allow researchers to design appropriate pharmacological strategies to treat brain ischemia.
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Roberts, Diane E., Archibald McNicol, and Ratna Bose. "Mechanism of Collagen Activation in Human Platelets." Journal of Biological Chemistry 279, no. 19 (February 23, 2004): 19421–30. http://dx.doi.org/10.1074/jbc.m308864200.
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The mechanism of collagen-induced human platelet activation was examined using Ca2+, Na+, and the pH-sensitive fluorescent dyes calcium green/fura red, sodium-binding benzofuran isophthalate, and 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Administration of a moderate dose of collagen (10 μg/ml) to human platelets resulted in an increase in [Ca2+]iand platelet aggregation. The majority of this increase in [Ca2+]iresulted from the influx of calcium from the extracellular milieu via the Na+/Ca2+exchanger (NCX) functioning in the reverse mode and was reduced in a dose-dependent manner by the NCX inhibitors 5-(4-chlorobenzyl)-2′,4′-dimethylbenzamil (KD50= 4.7 ± 1.1 μm) and KB-R7943 (KD50= 35.1 ± 4.8 μm). Collagen-induced platelet aggregation was dependent on an increase in [Ca2+]iand could be inhibited by chelation of intra- and extracellular calcium through the administration of 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) and EGTA, respectively, or via the administration of BAPTA-AM to platelets suspended in no-Na+/HEPES buffer. Collagen induced an increase in [Na+]i(23.2 ± 7.6 mm) via the actions of thromboxane A2and, to a lesser extent, of the Na+/H+exchanger. This study demonstrates that the collagen-induced increase in [Ca2+]iis dependent on the concentration of Na+in the extracellular milieu, indicating that the collagen-induced increase in [Na+]icauses the reversal of the NCX, ultimately resulting in an increase in [Ca2+]iand platelet aggregation.
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Geramipour, Amir, Zsófia Kohajda, Claudia Corici, János Prorok, Zsolt Szakonyi, Kinga Oravecz, Zoltán Márton, et al. "The investigation of the cellular electrophysiological and antiarrhythmic effects of a novel selective sodium–calcium exchanger inhibitor, GYKB-6635, in canine and guinea-pig hearts." Canadian Journal of Physiology and Pharmacology 94, no. 10 (October 2016): 1090–101. http://dx.doi.org/10.1139/cjpp-2015-0566.
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The sodium–calcium exchanger (NCX) is considered as the major transmembrane transport mechanism that controls Ca2+ homeostasis. Its contribution to the cardiac repolarization has not yet been directly studied due to lack of specific inhibitors, so that an urgent need for more selective compounds. In this study, the electrophysiological effects of GYKB-6635, a novel NCX inhibitor, on the NCX, L-type calcium, and main repolarizing potassium currents as well as action potential (AP) parameters were investigated. Ion currents and AP recordings were investigated by applying the whole-cell patch clamp and standard microelectrode techniques in canine heart at 37 °C. Effects of GYKB-6635 were studied in ouabain-induced arrhythmias in isolated guinea-pig hearts. At a concentration of 1 μmol/L, GYKB significantly reduced both the inward and outward NCX currents (57% and 58%, respectively). Even at a high concentration (10 μmol/L), GYKB-6635 did not change the ICaL, the maximum rate of depolarization (dV/dtmax), the main repolarizing K+ currents, and the main AP parameters. GYKB-6635 pre-treatment significantly delayed the time to the development of ventricular fibrillation (by about 18%). It is concluded that GYKB-6635 is a potent and highly selective inhibitor of the cardiac NCX and, in addition, it is suggested to also contribute to the prevention of DAD-based arrhythmias.
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Biner, Helena Lagger, Marie-Pierre Arpin-Bott, Johannes Loffing, Xiaoyan Wang, Mark Knepper, Steve C. Hebert, and Brigitte Kaissling. "Human Cortical Distal Nephron: Distribution of Electrolyte and Water Transport Pathways." Journal of the American Society of Nephrology 13, no. 4 (April 2002): 836–47. http://dx.doi.org/10.1681/asn.v134836.
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ABSTRACT. The exact distributions of the different salt transport systems along the human cortical distal nephron are unknown. Immunohistochemistry was performed on serial cryostat sections of healthy parts of tumor nephrectomized human kidneys to study the distributions in the distal convolution of the thiazide-sensitive Na-Cl cotransporter (NCC), the β subunit of the amiloride-sensitive epithelial Na channel (ENaC), the vasopressin-sensitive water channel aquaporin 2 (AQP2), and aquaporin 3 (AQP3), the H+ ATPase, the Na-Ca exchanger (NCX), plasma membrane calcium-ATPase, and calbindin-D28k (CaBP). The entire human distal convolution and the cortical collecting duct (CCD) display calbindin-D28k, although in variable amounts. Approximately 30% of the distal convolution profiles reveal NCC, characterizing the distal convoluted tubule. NCC overlaps with ENaC in a short portion at the end of the distal convoluted tubule. ENaC is displayed all along the connecting tubule (70% of the distal convolution) and the CCD. The major part of the connecting tubule and the CCD coexpress aquaporin 2 with ENaC. Intercalated cells, undetected in the first 20% of the distal convolution, were interspersed among the segment-specific cells of the remainder of the distal convolution, and of the CCD. The basolateral calcium extruding proteins, Na-Ca exchanger (NCX), and the plasma membrane Ca2+-ATPase were found all along the distal convolution, and, in contrast to other species, along the CCD, although in varying amounts. The knowledge regarding the precise distribution patterns of transport proteins in the human distal nephron and the knowledge regarding the differences from that in laboratory animals may be helpful for diagnostic purposes and may also help refine the therapeutic management of electrolyte disorders.
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Lowie, Bobbi-Jo, Xuan-Yu Wang, Elizabeth J. White, and Jan D. Huizinga. "On the origin of rhythmic calcium transients in the ICC-MP of the mouse small intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 301, no. 5 (November 2011): G835—G845. http://dx.doi.org/10.1152/ajpgi.00077.2011.
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Interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are pacemaker cells of the small intestine, producing the characteristic omnipresent electrical slow waves, which orchestrate peristaltic motor activity and are associated with rhythmic intracellular calcium oscillations. Our objective was to elucidate the origins of the calcium transients. We hypothesized that calcium oscillations in the ICC-MP are primarily regulated by the sarcoplasmic reticulum (SR) calcium release system. With the use of calcium imaging, study of the effect of T-type calcium channel blocker mibefradil revealed that T-type channels did not play a major role in generating the calcium transients. 2-Aminoethoxydiphenyl borate, an inositol 1,4,5 trisphosphate receptor (IP3R) inhibitor, and U73122, a phospholipase C inhibitor, both drastically decreased the frequency of calcium oscillations, suggesting a major role of IP3 and IP3-induced calcium release from the SR. Immunohistochemistry proved the expression of IP3R type I (IP3R-I), but not type II (IP3R-II) and type III (IP3R-III) in ICC-MP, indicating the involvement of the IP3R-I subtype in calcium release from the SR. Cyclopiazonic acid, a SR/endoplasmic reticulum calcium ATPase pump inhibitor, strongly reduced or abolished calcium oscillations. The Na-Ca exchanger (NCX) in reverse mode is likely involved in refilling the SR because the NCX inhibitor KB-R7943 markedly reduced the frequency of calcium oscillations. Immunohistochemistry revealed 100% colocalization of NCX and c-Kit in ICC-MP. Testing a mitochondrial NCX inhibitor, we were unable to show an essential role for mitochondria in regulating calcium oscillations in the ICC-MP. In summary, ongoing IP3 synthesis and IP3-induced calcium release from the SR, via the IP3R-I, are the major drivers of the calcium transients associated with ICC pacemaker activity. This suggests that a biochemical clock intrinsic to ICC determines the pacemaker frequency, which is likely directly linked to kinetics of the IP3-activated SR calcium channel and IP3 metabolism.
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Saini, Harjot K., and Naranjan S. Dhalla. "Sarcolemmal cation channels and exchangers modify the increase in intracellular calcium in cardiomyocytes on inhibiting Na+-K+-ATPase." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 1 (July 2007): H169—H181. http://dx.doi.org/10.1152/ajpheart.00007.2007.
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Although inhibition of the sarcolemmal (SL) Na+-K+-ATPase is known to cause an increase in the intracellular concentration of Ca2+ ([Ca2+]i) by stimulating the SL Na+/Ca2+ exchanger (NCX), the involvement of other SL sites in inducing this increase in [Ca2+]i is not fully understood. Isolated rat cardiomyocytes were treated with or without different agents that modify Ca2+ movements by affecting various SL sites and were then exposed to ouabain. Ouabain was observed to increase the basal levels of both [Ca2+]i and intracellular Na+ concentration ([Na+]i) as well as to augment the KCl-induced increases in both [Ca2+]i and [Na+]i in a concentration-dependent manner. The ouabain-induced changes in [Na+]i and [Ca2+]i were attenuated by treatment with inhibitors of SL Na+/H+ exchanger and SL Na+ channels. Both the ouabain-induced increase in basal [Ca2+]i and augmentation of the KCl response were markedly decreased when cardiomyocytes were exposed to 0–10 mM Na+. Inhibitors of SL NCX depressed but decreasing extracellular Na+ from 105–35 mM augmented the ouabain-induced increase in basal [Ca2+]i and the KCl response. Not only was the increase in [Ca2+]i by ouabain dependent on the extracellular Ca2+ concentration, but it was also attenuated by inhibitors of SL L-type Ca2+ channels and store-operated Ca2+ channels (SOC). Unlike the SL L-type Ca2+-channel blocker, the blockers of SL Na+ channel and SL SOC, when used in combination with SL NCX inhibitor, showed additive effects in reducing the ouabain-induced increase in basal [Ca2+]i. These results support the view that in addition to SL NCX, SL L-type Ca2+ channels and SL SOC may be involved in raising [Ca2+]i on inhibition of the SL Na+-K+-ATPase by ouabain. Furthermore, both SL Na+/H+ exchanger and Na+ channels play a critical role in the ouabain-induced Ca2+ increase in cardiomyocytes.
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Limbu, Bijay, Kushal Shah, Seth H. Weinberg, and Makarand Deo. "Role of Cytosolic Calcium Diffusion in Murine Cardiac Purkinje Cells." Clinical Medicine Insights: Cardiology 10s1 (January 2016): CMC.S39705. http://dx.doi.org/10.4137/cmc.s39705.
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Cardiac Purkinje cells (PCs) are morphologically and electrophysiologically different from ventricular myocytes and, importantly, exhibit distinct calcium (Ca2+) homeostasis. Recent studies suggest that PCs are more susceptible to action potential (AP) abnormalities than ventricular myocytes; however, the exact mechanisms are poorly understood. In this study, we utilized a detailed biophysical mathematical model of a murine PC to systematically examine the role of cytosolic Ca2+ diffusion in shaping the AP in PCs. A biphasic spatiotemporal Ca2+ diffusion process, as recorded experimentally, was implemented in the model. In this study, we investigated the role of cytosolic Ca2+ dynamics on AP and ionic current properties by varying the effective Ca2+ diffusion rate. It was observed that AP morphology, specifically the plateau, was affected due to changes in the intracellular Ca2+ dynamics. Elevated Ca2+ concentration in the sarcolemmal region activated inward sodium-Ca2+ exchanger (NCX) current, resulting in a prolongation of the AP plateau at faster diffusion rates. Artificially clamping the NCX current to control values completely reversed the alterations in the AP plateau, thus confirming the role of NCX in modifying the AP morphology. Our results demonstrate that cytosolic Ca2+ diffusion waves play a significant role in shaping APs of PCs and could provide mechanistic insights in the increased arrhythmogeneity of PCs.
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Giladi, Moshe, Reuben Hiller, Joel A. Hirsch, and Daniel Khananshvili. "Population Shift Underlies Ca2+-induced Regulatory Transitions in the Sodium-Calcium Exchanger (NCX)." Journal of Biological Chemistry 288, no. 32 (June 24, 2013): 23141–49. http://dx.doi.org/10.1074/jbc.m113.471698.
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Duman, Joseph G., Liangyi Chen, and Bertil Hille. "Calcium Transport Mechanisms of PC12 Cells." Journal of General Physiology 131, no. 4 (March 17, 2008): 307–23. http://dx.doi.org/10.1085/jgp.200709915.
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Many studies of Ca2+ signaling use PC12 cells, yet the balance of Ca2+ clearance mechanisms in these cells is unknown. We used pharmacological inhibition of Ca2+ transporters to characterize Ca2+ clearance after depolarizations in both undifferentiated and nerve growth factor-differentiated PC12 cells. Sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), plasma membrane Ca2+ ATPase (PMCA), and Na+/Ca2+ exchanger (NCX) account for almost all Ca2+ clearance in both cell states, with NCX and PMCA making the greatest contributions. Any contribution of mitochondrial uniporters is small. The ATP pool in differentiated cells was much more labile than that of undifferentiated cells in the presence of agents that dissipated mitochondrial proton gradients. Differentiated PC12 cells have a small component of Ca2+ clearance possessing pharmacological characteristics consistent with secretory pathway Ca2+ ATPase (SPCA), potentially residing on Golgi and/or secretory granules. Undifferentiated and differentiated cells are similar in overall Ca2+ transport and in the small transport due to SERCA, but they differ in the fraction of transport by PMCA and NCX. Transport in neurites of differentiated PC12 cells was qualitatively similar to that in the somata, except that the ER stores in neurites sometimes released Ca2+ instead of clearing it after depolarization. We formulated a mathematical model to simulate the observed Ca2+ clearance and to describe the differences between these undifferentiated and NGF-differentiated states quantitatively. The model required a value for the endogenous Ca2+ binding ratio of PC12 cell cytoplasm, which we measured to be 268 ± 85. Our results indicate that Ca2+ transport in undifferentiated PC12 cells is quite unlike transport in adrenal chromaffin cells, for which they often are considered models. Transport in both cell states more closely resembles that of sympathetic neurons, for which differentiated PC12 cells often are considered models. Comparison with other cell types shows that different cells emphasize different Ca2+ transport mechanisms.
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Oceandy, D., P. J. Stanley, E. J. Cartwright, and L. Neyses. "The regulatory function of plasma-membrane Ca2+-ATPase (PMCA) in the heart." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 927–30. http://dx.doi.org/10.1042/bst0350927.
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The PMCA (plasma-membrane Ca2+-ATPase) is a ubiquitously expressed calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. Unlike in non-excitable cells, where PMCA is the only system for calcium extrusion, in excitable cells, such as cardiomyocytes, PMCA has been shown to play only a minor role in calcium homoeostasis compared with the NCX (sodium/calcium exchanger), another system of calcium extrusion. However, increasing evidence points to an important role for PMCA in signal transduction; of particular interest in cardiac physiology is the modulation of nNOS (neuronal nitric oxide synthase) by isoform 4b of PMCA. In the present paper, we will discuss recent advances that support a key role for PMCA4 in modulating the nitric oxide signalling pathway in the heart.
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Ibáñez, Ignacio, David Bartolomé-Martín, Dolores Piniella, Cecilio Giménez, and Francisco Zafra. "Activity dependent internalization of the glutamate transporter GLT-1 requires calcium entry through the NCX sodium/calcium exchanger." Neurochemistry International 123 (February 2019): 125–32. http://dx.doi.org/10.1016/j.neuint.2018.03.012.
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Shlosman, Irina, Fabrizio Marinelli, José D. Faraldo-Gómez, and Joseph A. Mindell. "The prokaryotic Na+/Ca2+ exchanger NCX_Mj transports Na+ and Ca2+ in a 3:1 stoichiometry." Journal of General Physiology 150, no. 1 (December 13, 2017): 51–65. http://dx.doi.org/10.1085/jgp.201711897.
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Intracellular Ca2+ signals control a wide array of cellular processes. These signals require spatial and temporal regulation of the intracellular Ca2+ concentration, which is achieved in part by a class of ubiquitous membrane proteins known as sodium–calcium exchangers (NCXs). NCXs are secondary-active antiporters that power the translocation of Ca2+ across the cell membrane by coupling it to the flux of Na+ in the opposite direction, down an electrochemical gradient. Na+ and Ca2+ are translocated in separate steps of the antiport cycle, each of which is thought to entail a mechanism whereby ion-binding sites within the protein become alternately exposed to either side of the membrane. The prokaryotic exchanger NCX_Mj, the only member of this family with known structure, has been proposed to be a good functional and structural model of mammalian NCXs; yet our understanding of the functional properties of this protein remains incomplete. Here, we study purified NCX_Mj reconstituted into liposomes under well-controlled experimental conditions and demonstrate that this homologue indeed shares key functional features of the NCX family. Transport assays and reversal-potential measurements enable us to delineate the essential characteristics of this antiporter and establish that its ion-exchange stoichiometry is 3Na+:1Ca2+. Together with previous studies, this work confirms that NCX_Mj is a valid model system to investigate the mechanism of ion recognition and membrane transport in sodium–calcium exchangers.
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Wan, Qun-Fang, Everett Nixon, and Ruth Heidelberger. "Regulation of presynaptic calcium in a mammalian synaptic terminal." Journal of Neurophysiology 108, no. 11 (December 1, 2012): 3059–67. http://dx.doi.org/10.1152/jn.00213.2012.
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Ca2+ signaling in synaptic terminals plays a critical role in neurotransmitter release and short-term synaptic plasticity. In the present study, we examined the role of synaptic Ca2+ handling mechanisms in the synaptic terminals of mammalian rod bipolar cells, neurons that play a pivotal role in the high-sensitivity vision pathway. We found that mitochondria sequester Ca2+ under conditions of high Ca2+ load, maintaining intraterminal Ca2+ near resting levels. Indeed, the effect of the mitochondria was so powerful that the ability to clamp intraterminal Ca2+ with a somatically positioned whole cell patch pipette was compromised. The plasma membrane Ca2+-ATPase (PMCA), but not the Na+/Ca2+ exchanger (NCX) or the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), was an important regulator of resting Ca2+. Furthermore, PMCA activity, but not NCX or SERCA activity, was essential for the recovery of Ca2+ levels following depolarization-evoked Ca2+ entry. Loss of PMCA function was also associated with impaired restoration of membrane surface area following depolarization-evoked exocytosis. Given its roles in the regulation of intraterminal Ca2+ at rest and after a stimulus-evoked Ca2+ rise, the PMCA is poised to modulate luminance coding and adaptation to background illumination in the mammalian rod bipolar cell.
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Shenoy, Rajesh, Irwin Klein, and Kaie Ojamaa. "Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 4 (October 1, 2001): H1690—H1696. http://dx.doi.org/10.1152/ajpheart.2001.281.4.h1690.
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Thyroid hormone exerts positive inotropic effects on the heart mediated in part by its regulation of calcium transporter proteins, including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2), phospholamban (PLB), and Na+/Ca2+ exchanger (NCX). To further understand the potential cardiac chamber-specific effects of thyroid hormone action, we compared the triiodo-l-thyronine (T3) responsiveness of calcium transporter proteins in atrial versus ventricular tissues. Rats were rendered hypothyroid by ingestion of propylthiouracil, and a subgroup of animals was treated with T3 for 7 days (7 μg/day by constant infusion). Atrial and left ventricular (LV) tissue homogenates were analyzed for expression of SERCA2, PLB, and NCX proteins by Western blot analysis. SERCA2 protein significantly decreased by 50% in hypothyroid LV and was normalized by T3 treatment. In contrast, SERCA2 protein in atria was unaltered in the hypothyroid state. PLB protein expression significantly increased by 1.6- and 5-fold in the hypothyroid LV and atria, respectively, and returned to euthyroid levels with T3 treatment. Expression of NCX protein showed a greater response to T3 treatment in atria tissue than in ventricular tissue. Sarcoplasmic reticulum calcium cycling is determined in part by the ratio of SERCA2 to PLB. This ratio was sixfold higher in the atria compared with LV, suggesting that PLB may play a minor role in the regulation of SERCA2 function in normal atria. We conclude that calcium transporter proteins are responsive to thyroid hormone in a chamber-specific manner, with atria showing a greater change in protein content in response to T3. The differential effect on atria may account for the occurrence of atrial rather than ventricular arrhythmias in response to even mild degrees of thyrotoxicosis.
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Zhang, Zijuan, Shuguang Sun, Caixia Du, Wei Li, Juan Zhang, Yanqin Zhu, Peilin Liu, and Ying Xing. "Effects of Leptin on Na+/Ca2+ Exchanger in PC12 Cells." Cellular Physiology and Biochemistry 40, no. 6 (2016): 1529–37. http://dx.doi.org/10.1159/000453203.
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Background/Aims: Alzheimer's disease (AD) is known to be related to alterations in neuronal intracellular calcium activity ([Ca2+]i). The present study revealed the distinct role of leptin in Na+/Ca2+-exchanger activity. Methods: [Ca2+]i was determined utilizing Fura-2 fluorescence. The activity of NCX was measured by removal of extracellular Na+ in the presence of external Ca2+. Na+/Ca2+-exchanger activity was further quantified from whole cell currents following removal of extracellular Na+. Na+/Ca2+-exchanger isoform NCX1 transcript levels and protein abundance were quantified by RT-PCR and Western blotting, respectively. Results: Exposure of PC12 cells to 30 µM amyloid (Aβ42) increased [Ca2+]i, an effect significantly blunted by 6 hours incubation with leptin before Aβ42 treatment. Moreover, leptin treatment significantly increased Na+/Ca2+-exchanger mediated Ca+ transport and current, NCX1 transcript level as well as NCX1 membrane protein abundance. Conclusion: We show that leptin blunts Aβ42-evoked [Ca2+]i increase by increasing expression and activity of Na+/Ca2+-exchanger NCX1.
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Newton, Jamila, Luli Rebecca Akinfiresoye, and Prosper N’Gouemo. "Inhibition of the Sodium Calcium Exchanger Suppresses Alcohol Withdrawal-Induced Seizure Susceptibility." Brain Sciences 11, no. 2 (February 23, 2021): 279. http://dx.doi.org/10.3390/brainsci11020279.
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Calcium influx plays important roles in the pathophysiology of seizures, including acoustically evoked alcohol withdrawal-induced seizures (AWSs). One Ca2+ influx route of interest is the Na+/Ca2+ exchanger (NCX) that, when operating in its reverse mode (NCXrev) activity, can facilitate Ca2+ entry into neurons, possibly increasing neuronal excitability that leads to enhanced seizure susceptibility. Here, we probed the involvement of NCXrev activity on AWS susceptibility by quantifying the effects of SN-6 and KB-R7943, potent blockers of isoform type 1 (NCX1rev) and 3 (NCX3rev), respectively. Male, adult Sprague–Dawley rats were used. Acoustically evoked AWSs consisted of wild running seizures (WRSs) that evolved into generalized tonic–clonic seizures (GTCSs). Quantification shows that acute SN-6 treatment at a relatively low dose suppressed the occurrence of the GTCSs (but not WRSs) component of AWSs and markedly reduced the seizure severity. However, administration of KB-R7943 at a relatively high dose only reduced the incidence of GTCSs. These findings demonstrate that inhibition of NCX1rev activity is a putative mechanism for the suppression of alcohol withdrawal-induced GTCSs.
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Romero, Jose R., Dennis A. Ricupero, Alicia Rivera, Ronald H. Goldstein, and Paul R. Conlin. "Activation of Na + /Ca 2+ Exchanger in Kinin B 1 Receptor-Stimulated Human Fibroblast Is Associated with Collagen Production." Hypertension 36, suppl_1 (October 2000): 710–20. http://dx.doi.org/10.1161/hyp.36.suppl_1.710.
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P148 The arterial wall in hypertension is characterized by thickening of the media, in part due to increased deposition of connective tissue. Autocrine and paracrine factors may participate in this process; including products of the kallikrein-kinin system. We evaluated early signal transduction events and effects on collagen formation in B 1 -stimulated human myofibroblast cells (IMR-90). We measured cytosolic calcium (Ca cyt ) levels in cells loaded with FURA-2AM. Gene expression of connective tissue growth factor (CTGF) and α1(I) collagen was determined by estimating mRNA levels using Northern analysis of B 1 stimulated cells. Activation of the B 1 receptor with des-arg 10 -kallidin stimulated a three-fold increase in CTGF mRNA by increasing its stability. Furthermore, B 1 receptor activation caused an increase in α1(I) collagen mRNA and a four-fold increase in type I collagen synthesis in these cells; events not observed in B 2 receptor-stimulated cells. Activation of the B 1 receptor stimulated a dose dependent rise in Ca cyt (EC 50 =1.9nM) which was completely inhibited by des-arg 10 -[leu 9 ]-kallidin (100nM), a B 1 receptor antagonist. Isosmotic replacement of extracellular Na + with N -methyl,D-glucamine blocked > 90% of the B 1 stimulated rise in Ca cyt . A similar effect was observed when Ca 2+ was removed from the extracellular media, suggesting a role for the plasma membrane Na + /Ca 2+ exchanger (NCX). To further define a role for the NCX on CTGF formation we used dichlorobenzamil (DCB) and KB-R7943, two specific NCX inhibitors. DCB completely blocked the activation of B 1 receptor induced increase in CTGF mRNA stability while not affecting basal CTGF mRNA levels. In contrast, preincubation with EIPA, an amiloride analog, did not affect basal or stimulated CTGF mRNA levels. Furthermore, 60μM KB-R7943 blocked the B 1 stimulated rise in Ca cyt . NCX isoform 1 was identified in these cells using RT-PCR and immuno-detection. Thus, B 1 receptor stimulation increases fibrogenesis through a mechanism that involves modulation of cation metabolism via reverse-mode activation of NCX.
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Wheatly, M., Z. Zhang, J. Weil, J. Rogers, and L. Stiner. "Novel subcellular and molecular tools to study Ca(2+) transport mechanisms during the elusive moulting stages of crustaceans: flow cytometry and polyclonal antibodies." Journal of Experimental Biology 204, no. 5 (March 1, 2001): 959–66. http://dx.doi.org/10.1242/jeb.204.5.959.
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Our understanding of calcium homeostasis during the crustacean moulting cycle derives from research on intermoult animals that has been extrapolated to other stages. In terms of transepithelial Ca(2+) flux, the more interesting stages are those surrounding ecdysis since crustaceans experience a sizeable negative calcium balance in immediate premoult and a significant positive calcium balance in immediate postmoult. These stages are elusive in the sense that larger species such as lobsters are rarely captured at this time, and smaller species such as blue crabs and crayfish are seldom synchronized in their moulting cycle. The reductionist approaches employed in cellular physiology, such as vesicle techniques, employ pooling of fresh tissues from many organisms. Examination of the elusive moulting stages requires more sensitive approaches that can utilize tissue from an individual crustacean to characterize Ca(2+) pumps (Sarco/Endoplasmic Reticulum Ca(2+)-ATPase, SERCA; Plasma Membrane Ca(2+)-ATPase, PMCA) and the Na(+)/Ca(2+) eXchanger (NCX). An emerging subcellular approach described in this paper is to use flow cytometry as a technique to monitor Ca(2+) uptake into Fluo-3-loaded membrane vesicles. This paper illustrates the utility of this technique for measuring ATP-dependent Ca(2+) uptake into hepatopancreatic basolateral membrane vesicles. Obstacles to progress in molecular studies have not been limited by synchronization of moulting since tissue can be snap-frozen and collected from many animals over time. Here, the problem has been the lack of specific antibodies that hybridize with the Ca(2+) transporters of interest so that they can be localized within epithelia. In this paper, we introduce polyclonal antibodies raised in rabbits against crayfish SERCA, PMCA and NCX. Immunocytochemistry of SERCA in muscle, PMCA in antennal gland and NCX in heart confirms the specificity of the antibodies.
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Liu, Ai-Hua, Yi-Min Bao, Xing-Yu Wang, and Zhi-Xiong Zhang. "Cardio-Protection by Ginkgo biloba Extract 50 in Rats with Acute Myocardial Infarction is Related to Na+–Ca2+ Exchanger." American Journal of Chinese Medicine 41, no. 04 (January 2013): 789–800. http://dx.doi.org/10.1142/s0192415x13500535.
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Ginkgo biloba has been used for medical purposes for centuries in traditional Chinese medicine. Ginkgo biloba extract 50 (GBE50) is a new standardized GBE product that matches the standardized German product as EGb761. This paper is aimed at studying the cardio-protection effects of GBE50 Salvia miltiorrhiza on myocardial function, area at risk, myocardial ultra-structure, and expression of calcium handling proteins in rat ischemic myocardium. Myocardium ischemia was induced by the left anterior descending (LAD) coronary artery occlusion and myocardial function was recorded by a transducer advanced into the left ventricle on a computer system. In vitro myocardial infarction was measured by 2,3,5-triphenyltetrazolium chloride (TTC) and Evans blue staining of heart sections. Morphological change was evaluated by electric microscopy and Western blotting was used for protein expression. Hemodynamic experiments in vivo showed that postischemic cardiac contractile function was reduced in ischemic rats. Salvia miltiorrhiza (7.5 g/kg/d×7) and Ginkgo biloba extract 50 (GBE50) (100 mg/kg/d×7) improved post-schemic cardiac diastolic dysfunction while not affecting the systolic function. In hearts of GBE50 group and Salvia miltiorrhiza (SM) group, the area at risk was significantly reduced and myocardial structure was better-preserved. Moreover, Na +– Ca 2+ exchanger (NCX) expression increase and sarcoplasmic reticulum Ca 2+– ATPase 2 (SERCA2), LTCC, and ryanodine receptor 2 (RyR2) expression decreases were smaller than those in ischemia group. There was a significant difference between the GBE50 and ischemia group in NCX expression. GBE50 could improve recovery in contractile function and prevent myocardium from ischemia damage, which may be caused by attenuating the abnormal expression of NCX.
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Plank, David M., Atsuko Yatani, Honda Ritsu, Sandra Witt, Betty Glascock, M. Jane Lalli, Muthu Periasamy, et al. "Calcium dynamics in the failing heart: restoration by β-adrenergic receptor blockade." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H305—H315. http://dx.doi.org/10.1152/ajpheart.00425.2002.
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Changes in calcium (Ca2+) regulation contribute to loss of contractile function in dilated cardiomyopathy. Clinical treatment using β-adrenergic receptor antagonists (β-blockers) slows deterioration of cardiac function in end-stage heart failure patients; however, the effects of β-blocker treatment on Ca2+ dynamics in the failing heart are unknown. To address this issue, tropomodulin-overexpressing transgenic (TOT) mice, which suffer from dilated cardiomyopathy, were treated with a nonselective β-receptor blocker (5 mg · kg-1 · day-1 propranolol) for 2 wk. Ca2+ dynamics in isolated cardiomyocytes of TOT mice significantly improved after treatment compared with untreated TOT mice. Frequency-dependent diastolic and Ca2+ transient amplitudes were returned to normal in propranolol-treated TOT mice and but not in untreated TOT mice. Ca2+ kinetic measurements of time to peak and time decay of the caffeine-induced Ca2+ transient to 50% relaxation were also normalized. Immunoblot analysis of untreated TOT heart samples showed a 3.6-fold reduction of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), whereas Na+/Ca2+ exchanger (NCX) concentrations were increased 2.6-fold relative to nontransgenic samples. Propranolol treatment of TOT mice reversed the alterations in SERCA and NCX protein levels but not potassium channels. Although restoration of Ca2+ dynamics occurred within 2 wk of β-blockade treatment, evidence of functional improvement in cardiac contractility assessed by echocardiography took 10 wk to materialize. These results demonstrate that β-adrenergic blockade restores Ca2+ dynamics and normalizes expression of Ca2+-handling proteins, eventually leading to improved hemodynamic function in cardiomyopathic hearts.
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Estacion, M., B. P. S. Vohra, S. Liu, J. Hoeijmakers, C. G. Faber, I. S. J. Merkies, G. Lauria, J. A. Black, and S. G. Waxman. "Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation." Journal of Neurophysiology 114, no. 3 (September 2015): 1554–64. http://dx.doi.org/10.1152/jn.00195.2015.
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Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na+ concentration ([Na+]) and intracellular [Ca2+] following stimulation with high [K+] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca2+] transients evoked by high [K+] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K+] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K+] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca2+ or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K+] and 2-DG. These results point to [Na+] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca2+ toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.
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Moonga, Baljit S., Robert Davidson, Li Sun, Olugbenga A. Adebanjo, James Moser, Mohammad Abedin, Neeha Zaidi, Christopher L. H. Huang, and Mone Zaidi. "Identification and Characterization of a Sodium/Calcium Exchanger, NCX-1, in Osteoclasts and Its Role in Bone Resorption." Biochemical and Biophysical Research Communications 283, no. 4 (May 2001): 770–75. http://dx.doi.org/10.1006/bbrc.2001.4870.
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Li, Jing-Ping, Hiroshi Kajiya, Fujio Okamoto, Akihiro Nakao, Takahiro Iwamoto, and Koji Okabe. "Three Na+/Ca2+Exchanger (NCX) Variants Are Expressed in Mouse Osteoclasts and Mediate Calcium Transport during Bone Resorption." Endocrinology 148, no. 5 (May 2007): 2116–25. http://dx.doi.org/10.1210/en.2006-1321.
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Huang, Jingbo, Leif Hove-Madsen, and Glen F. Tibbits. "SR Ca2+ refilling upon depletion and SR Ca2+ uptake rates during development in rabbit ventricular myocytes." American Journal of Physiology-Cell Physiology 293, no. 6 (December 2007): C1906—C1915. http://dx.doi.org/10.1152/ajpcell.00241.2007.
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While it has been reported that a sparse sarcoplasmic reticulum (SR) and a low SR Ca2+ pump density exist at birth, we and others have recently shown that significant amounts of Ca2+ are stored in the neonatal rabbit heart SR. Here we try to determine developmental changes in SR Ca2+ loading mechanisms and Ca2+ pump efficacy in rabbit ventricular myocytes. SR Ca2+ loading (loadSR) and k0.5 (Ca2+ concentration at half-maximal SR Ca2+ uptake) were higher and lower, respectively, in younger age groups. Inhibition of the L-type calcium current ( ICa) with 15 μM nifedipine dramatically reduced loadSR in older but not in younger age groups. In contrast, subsequent inhibition of the Na+/Ca2+ exchanger (NCX) with 10 μM KB-R7943 strongly reduced loadSR in the younger but not the older age groups. Accordingly, the time integral of the inward NCX current (tail INCX) elicited on repolarization was highly sensitive to nifedipine in the older groups and sensitive to KB-R7943 in the younger groups. Interestingly, slow SR loading took place in the presence of both nifedipine and KB-R7943 in all age groups, although it was less prominent in the older groups. We conclude that the SR loading capacity at the earliest postnatal stages is at least as large as that of adult myocytes. However, reverse-mode NCX plays a prominent role in SR Ca2+ loading at early postnatal stages while ICa is the main source of SR Ca2+ loading at late postnatal and adult stages.
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TEWARI, SHIVENDRA G., and K. R. PARDASANI. "MODELING EFFECT OF SODIUM PUMP ON CALCIUM OSCILLATIONS IN NEURON CELLS." Journal of Multiscale Modelling 04, no. 03 (September 2012): 1250010. http://dx.doi.org/10.1142/s1756973712500102.
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Calcium plays a significant role in a number of processes like muscle contraction, gene expression, synaptic plasticity, signal transduction etc. but the significance of calcium oscillation is not yet completely understood in most of the cell types. A number of investigators have reported the oscillatory behavior of calcium due to intracellular concentration of inositol 1,4,5-trisphosphate (IP3). In this paper, an attempt has been made to study the oscillations induced in calcium due to dynamically changing membrane potential with special relevance to sodium pump. A mathematical model is developed which incorporates nearly all important and necessary biophysical components like L-type calcium channel, sodium channel, potassium channel, cytosolic buffers, calcium pump, sodium–calcium exchanger (NCX), sodium–potassium ATPase (sodium pump), and dynamic membrane potential. These channels have realistic gating mechanism and emulate the gating mechanism proposed in the famous paper of Hodgkin and Huxley.1 The model leads to an initial value problem involving system of non-linear ordinary differential equations. A numerical solution has been obtained using Gear's method. The numerical results have been used to study the effect of sodium pump over the frequency of Ca 2+ oscillation. At lower and higher sodium pump current densities the Ca 2+ oscillation frequency is observed to be 278 Hz and 225 Hz respectively.
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Armoundas, Antonis A., Jochen Rose, Rajesh Aggarwal, Bruno D. Stuyvers, Brian O'Rourke, David A. Kass, Eduardo Marbán, Stephen R. Shorofsky, Gordon F. Tomaselli, and C. William Balke. "Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 3 (March 2007): H1607—H1618. http://dx.doi.org/10.1152/ajpheart.00525.2006.
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Myocytes from the failing myocardium exhibit depressed and prolonged intracellular Ca2+ concentration ([Ca2+]i) transients that are, in part, responsible for contractile dysfunction and unstable repolarization. To better understand the molecular basis of the aberrant Ca2+ handling in heart failure (HF), we studied the rabbit pacing tachycardia HF model. Induction of HF was associated with action potential (AP) duration prolongation that was especially pronounced at low stimulation frequencies. L-type calcium channel current ( ICa,L) density (−0.964 ± 0.172 vs. −0.745 ± 0.128 pA/pF at +10 mV) and Na+/Ca2+ exchanger (NCX) currents (2.1 ± 0.8 vs. 2.3 ± 0.8 pA/pF at +30 mV) were not different in myocytes from control and failing hearts. The amplitude of peak [Ca2+]i was depressed (at +10 mV, 0.72 ± 0.07 and 0.56 ± 0.04 μM in normal and failing hearts, respectively; P < 0.05), with slowed rates of decay and reduced Ca2+ spark amplitudes ( P < 0.0001) in myocytes isolated from failing vs. control hearts. Inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a revealed a greater reliance on NCX to remove cytosolic Ca2+ in myocytes isolated from failing vs. control hearts ( P < 0.05). mRNA levels of the α1C-subunit, ryanodine receptor (RyR), and NCX were unchanged from controls, while SERCA2a and phospholamban (PLB) were significantly downregulated in failing vs. control hearts ( P < 0.05). α1C protein levels were unchanged, RyR, SERCA2a, and PLB were significantly downregulated ( P < 0.05), while NCX protein was significantly upregulated ( P < 0.05). These results support a prominent role for the sarcoplasmic reticulum (SR) in the pathogenesis of HF, in which abnormal SR Ca2+ uptake and release synergistically contribute to the depressed [Ca2+]i and the altered AP profile phenotype.
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Moon, H. S., E. Choi, and C. Hyun. "The Cardiac Sodium-Calcium Exchanger Gene (NCX-1) is a Potential Canine Cardiac Biomarker of Chronic Mitral Valvular Insufficiency." Journal of Veterinary Internal Medicine 22, no. 6 (November 2008): 1360–65. http://dx.doi.org/10.1111/j.1939-1676.2008.0209.x.
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JHA, AMRITA, NEERU ADLAKHA, and BRAJESH KUMAR JHA. "FINITE ELEMENT MODEL TO STUDY EFFECT OF Na+−Ca2+ EXCHANGERS AND SOURCE GEOMETRY ON CALCIUM DYNAMICS IN A NEURON CELL." Journal of Mechanics in Medicine and Biology 16, no. 02 (March 2016): 1650018. http://dx.doi.org/10.1142/s0219519416500184.
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The study of calcium diffusion in neuron cells has gained interest among research workers during the last two decades, due to its wide variety of roles in human body like muscle contraction, secretion, metabolism, signal transduction etc. Na[Formula: see text] is the first ion that comes in the hierarchy of ions affecting cytosolic Ca[Formula: see text] concentration. This Na[Formula: see text] ion helps in intracellular Ca[Formula: see text] regulation in cytosol via Na[Formula: see text]/Ca[Formula: see text] exchanger protein (NCX protein). Most of the theoretical investigations on calcium diffusion in neuron cells have been carried out for one and two dimensional cases by various research workers and that too by incorporating a point source of influx. In order to have more realistic study the more details of geometry, microstructure and physiological parameters need to be incorporated in the models. In view of above a three dimensional unsteady state model of Calcium dynamics in a neuron cell has been developed. Apart from the point source, the line and surface sources of an influx of Ca[Formula: see text]as well as the Na[Formula: see text]/Ca[Formula: see text] exchanger, have been incorporated in the model. Appropriate initial and boundary conditions have been framed. The region is discretized using three dimensional circular sectoral elements. Variational finite element method has been employed to obtain the solution. The numerical results have been computed to study effect of Na[Formula: see text]/Ca[Formula: see text] exchanger, point source, line source and surface source of an influx on Ca[Formula: see text] distribution in a neuron cell.
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Pallafacchina, Giorgia, Sofia Zanin, and Rosario Rizzuto. "Recent advances in the molecular mechanism of mitochondrial calcium uptake." F1000Research 7 (November 28, 2018): 1858. http://dx.doi.org/10.12688/f1000research.15723.1.
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In the last few decades, a large body of experimental evidence has highlighted the complex role for mitochondria in eukaryotic cells: they are not only the site of aerobic metabolism (thus providing most of the ATP supply for endergonic processes) but also a crucial checkpoint of cell death processes (both necrosis and apoptosis) and autophagy. For this purpose, mitochondria must receive and decode the wide variety of physiological and pathological stimuli impacting on the cell. The “old” notion that mitochondria possess a sophisticated machinery for accumulating and releasing Ca2+, the most common and versatile second messenger of eukaryotic cells, is thus no surprise. What may be surprising is that the identification of the molecules involved in mitochondrial Ca2+ transport occurred only in the last decade for both the influx (the mitochondrial Ca2+ uniporter, MCU) and the efflux (the sodium calcium exchanger, NCX) pathways. In this review, we will focus on the description of the amazing molecular complexity of the MCU complex, highlighting the numerous functional implications of the tissue-specific expression of the variants of the channel pore components (MCU/MCUb) and of the associated proteins (MICU 1, 2, and 3, EMRE, and MCUR1).