Na+/Ca2+ exchange and Na+/K+‐ATPase in the heart

Shattock, Michael J.; Ottolia, Michela; Bers, Donald M.; Blaustein, Mordecai P.; Boguslavskyi, Andrii; Bossuyt, Julie; Bridge, John H.B.; Chen‐Izu, Ye; Clancy, Colleen E.; Edwards, Andrew G.; Goldhaber, Joshua I.; Kaplan, Jack H.; Lingrel, Jerry B.; Pavlović, Davor; Philipson, Kenneth D.; Sipido, Karin R.; Xie, Zili

doi:10.1113/jphysiol.2014.282319

Cited by 173 publications

(168 citation statements)

References 252 publications

(531 reference statements)

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“…The increased intracellular Ca 2+ will also activate NCX expressed in ASM [41,42]. We found that when NCX was inhibited by replacing Na + with Li + , the TEA-induced oscillatory contractions were transiently enhanced and then disappeared (Fig.…”

Section: Figmentioning

confidence: 81%

See 1 more Smart Citation

Generation and Role of Oscillatory Contractions in Mouse Airway Smooth Muscle

Xu¹,

Zhao²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Tetraethylammonium chloride (TEA) induces oscillatory contractions in mouse airway smooth muscle (ASM); however, the generation and maintenance of oscillatory contractions and their role in ASM are unclear. Methods: In this study, oscillations of ASM contraction and intracellular Ca²⁺ were measured using force measuring and Ca²⁺ imaging technique, respectively. TEA, nifedipine, niflumic acid, acetylcholine chloride, lithium chloride, KB-R7943, ouabain, 2-Aminoethoxydiphenyl borate, thapsigargin, tetrodotoxin, and ryanodine were used to assess the mechanism of oscillatory contractions. Results: TEA induced depolarization, resulting in activation of L-type voltage-dependent Ca²⁺ channels (LVDCCs) and voltage-dependent Na⁺ (V_Na) channels. The former mediated Ca²⁺ influx to trigger a contraction and the latter mediated Na⁺ entry to enhance the contraction via activating LVDCCs. Meanwhile, increased Ca²⁺-activated Cl^- channels, inducing depolarization that resulted in contraction through LVDCCs. In addition, the contraction was enhanced by intracellular Ca²⁺ release from Ca²⁺ stores mediated by inositol (1,4,5)-trisphosphate receptors (IP₃Rs). These pathways together produce the contractile phase of the oscillatory contractions. Furthermore, the increased Ca²⁺ activated the Na⁺-Ca²⁺ exchanger (NCX), which transferred Ca²⁺ out of and Na⁺ into the cells. The former induced relaxation and the latter activated Na⁺/K⁺-ATPase that induced hypopolarization to inactivate LVDCCs causing further relaxation. This can also explain the relaxant phase of the oscillatory contractions. Moreover, the depolarization induced by V_Na channels and NCX might be greater than the hypopolarization caused by Na⁺/K⁺-ATPase alone, inducing LVDCC activation and resulting in further contraction. Conclusions: These data indicate that the TEA-induced oscillatory contractions were cooperatively produced by LVDCCs, V_Na channels, Ca²⁺-activated Cl^- channels, NCX, Na⁺/K⁺ ATPase, IP₃Rs-mediated Ca²⁺ release, and extracellular Ca²⁺.

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Section: Figmentioning

confidence: 81%

“…In addition, NCX will induce cytosolic Na + increases, which will then activate Na + /K + -ATPase [42,43]. Following the inhibition of this enzyme by ouabain, a larger contraction was observed and the oscillatory contractions then vanished (Fig.…”

Section: Figmentioning

confidence: 99%

Generation and Role of Oscillatory Contractions in Mouse Airway Smooth Muscle

Xu¹,

Zhao²,

Zhang³

et al. 2018

Cell Physiol Biochem

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“…As a result of this mechanism, the junctional cleft is primed with Ca 2+ , facilitating EC-coupling. During diastole, cytosolic Ca 2+ increases from RyR2 activation promote Ca 2+ extrusion through NCX activity [37]. …”

Section: Ec Coupling and Hfmentioning

confidence: 99%

“…It has been proposed that NCX activity is up-regulated in failing heart [38], but divergent evidence also exists [37]. SR Ca 2+ leak increases cytosolic Ca 2+ and forward mode-dependent Ca 2+ extrusion, exacerbating declines in SR Ca 2+ and promoting Na + entry [13].…”

Section: Ec Coupling and Hfmentioning

confidence: 99%

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

Cho

Altamirano

Hill

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Robust successes have been achieved in recent years in conquering the acutely lethal manifestations of heart disease. Many patients who previously would have died now survive to enjoy happy and productive lives. Nevertheless, the devastating impact of heart disease continues unabated, as the spectrum of disease has evolved with new manifestations. In light of this ever-evolving challenge, insights that culminate in novel therapeutic targets are urgently needed. Here, we review fundamental mechanisms of heart failure, both with reduced (HFrEF) and preserved (HFpEF) ejection fraction. We discuss pathways that regulate cardiomyocyte remodeling and turnover, focusing on Ca2+ signaling, autophagy, and apoptosis. In particular, we highlight recent insights pointing to novel connections among these events. We also explore mechanisms whereby potential therapeutic approaches targeting these processes may improve morbidity and mortality in the devastating syndrome of heart failure.

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“…The eukaryotic exchanger is composed of 10 transmembrane domains (TM) (11,12), with a large cytosolic loop between TM5 and TM6. Deletion of the cytosolic loop has revealed that it does not play a direct role in ion translocation, but rather it mediates regulation of the exchanger by associating with various cytosolic factors (13)(14)(15)(16).…”

mentioning

confidence: 99%

Protein Phosphatase 1c Associated with the Cardiac Sodium Calcium Exchanger 1 Regulates Its Activity by Dephosphorylating Serine 68-phosphorylated Phospholemman

Hafver

Hodne

Wanichawan

et al. 2016

Journal of Biological Chemistry

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The sodium (Na ؉ )-calcium (Ca 2؉ ) exchanger 1 (NCX1) is an important regulator of intracellular Ca 2؉ homeostasis. Serine 68-phosphorylated phospholemman (pSer-68-PLM) inhibits NCX1 activity. In the context of Na ؉ /K ؉ -ATPase (NKA) regulation, pSer-68-PLM is dephosphorylated by protein phosphatase 1 (PP1). PP1 also associates with NCX1; however, the molecular basis of this association is unknown. In this study, we aimed to analyze the mechanisms of PP1 targeting to the NCX1-pSer-68-PLM complex and hypothesized that a direct and functional NCX1-PP1 interaction is a prerequisite for pSer-68-PLM dephosphorylation. Using a variety of molecular techniques, we show that PP1 catalytic subunit (PP1c) co-localized, co-fractionated, and co-immunoprecipitated with NCX1 in rat cardiomyocytes, left ventricle lysates, and HEK293 cells. Bioinformatic analysis, immunoprecipitations, mutagenesis, pulldown experiments, and peptide arrays constrained PP1c anchoring to the K(I/V)FF motif in the first Ca 2؉ binding domain (CBD) 1 in NCX1. This binding site is also partially in agreement with the extended PP1-binding motif K(V/I)FF-X 5-8 ⌽ 1 ⌽ 2 -X 8 -9 -R. The cytosolic loop of NCX1, containing the K(I/V)FF motif, had no effect on PP1 activity in an in vitro assay. Dephosphorylation of pSer-68-PLM in HEK293 cells was not observed when NCX1 was absent, when the K(I/V)FF motif was mutated, or when the PLM-and PP1c-binding sites were separated (mimicking calpain cleavage of NCX1). Co-expression of PLM and NCX1 inhibited NCX1 current (both modes). Moreover, co-expression of PLM with NCX1(F407P) (mutated K(I/V)FF motif) resulted in the current being completely abolished. In conclusion, NCX1 is a substrate-specifying PP1c regulator protein, indirectly regulating NCX1 activity through pSer-68-PLM dephosphorylation.

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Na⁺/Ca²⁺ exchange and Na⁺/K⁺‐ATPase in the heart

Cited by 173 publications

References 252 publications

Generation and Role of Oscillatory Contractions in Mouse Airway Smooth Muscle

Generation and Role of Oscillatory Contractions in Mouse Airway Smooth Muscle

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

Protein Phosphatase 1c Associated with the Cardiac Sodium Calcium Exchanger 1 Regulates Its Activity by Dephosphorylating Serine 68-phosphorylated Phospholemman

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