scholarly journals Targeting and Stability of Na/Ca Exchanger 1 in Cardiomyocytes Requires Direct Interaction with the Membrane Adaptor Ankyrin-B

2006 ◽  
Vol 282 (7) ◽  
pp. 4875-4883 ◽  
Author(s):  
Shane R. Cunha ◽  
Naina Bhasin ◽  
Peter J. Mohler
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Direct Interaction ◽  
Binding Activity ◽  
Membrane Domains ◽  
Excitable Cells ◽  
Expression Activity ◽  
Cellular Pathways ◽  
Ankyrin B ◽  
Calcium Extrusion

Na/Ca exchanger activity is important for calcium extrusion from the cardiomyocyte cytosol during repolarization. Animal models exhibiting altered Na/Ca exchanger expression display abnormal cardiac phenotypes. In humans, elevated Na/Ca exchanger expression/activity is linked with pathophysiological conditions including arrhythmia and heart failure. Whereas the molecular mechanisms underlying Na/Ca exchanger biophysical properties are widely studied and generally well characterized, the cellular pathways and molecular partners underlying the specialized membrane localization of Na/Ca exchanger in cardiac tissue are essentially unknown. In this report, we present the first direct evidence for a protein pathway required for Na/Ca exchanger localization and stability in primary cardiomyocytes. We define the minimal structural requirements on ankyrin-B for direct Na/Ca exchanger interactions. Moreover, using ankyrin-B mutants that lack Na/Ca exchanger binding activity, and primary cardiomyocytes with reduced ankyrin-B expression, we demonstrate that direct interaction with the membrane adaptor ankyrin-B is required for the localization and post-translational stability of Na/Ca exchanger 1 in neonatal mouse cardiomyocytes. These results raise exciting new questions regarding potentially dynamic roles for ankyrin proteins in the biogenesis and maintenance of specialized membrane domains in excitable cells.

scholarly journals Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis

2013 ◽  
Vol 304 (9) ◽  
pp. H1253-H1266 ◽  
Author(s):  
Roseanne M. Wolf ◽  
Patric Glynn ◽  
Seyed Hashemi ◽  
Keyan Zarei ◽  
Colleen C. Mitchell ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Sinus Node ◽  
Ion Homeostasis ◽  
Atrial Arrhythmias ◽  
Excitable Cells ◽  
Tissue Mass ◽  
Exit Block ◽  
Ankyrin B ◽  
Increased Susceptibility

Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca2+ channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na+/Ca2+ exchanger and Na+/K+ ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction.

scholarly journals Giant ankyrin-B suppresses stochastic collateral axon branching through direct interaction with microtubules

2020 ◽  
Vol 219 (8) ◽  
Author(s):  
Keyu Chen ◽  
Rui Yang ◽  
Yubing Li ◽  
Jin Chuan Zhou ◽  
Mingjie Zhang
Keyword(s):  
Tandem Repeats ◽  
Direct Interaction ◽  
Binding Activity ◽  
Axon Collateral ◽  
Axon Branching ◽  
Microtubule Binding ◽  
Ankyrin G ◽  
Binding Avidity ◽  
Ankyrin B

Giant ankyrin-B (gAnkB) is a 440-kD neurospecific ankyrin-B isoform and a high-confidence target for autism mutations. gAnkB suppresses axon branching through coordination of cortical microtubules, and autism-related mutation of gAnkB results in ectopic neuronal connectivity. We identified a bipartite motif from gAnkB, which bundles and avidly binds to microtubules in vitro. This motif is composed of a module of 15 tandem repeats followed by a short, conserved fragment also found in giant ankyrin-G (BG-box). Combination of these two parts synergistically increases microtubule-binding avidity. Transfection of astrocytes (which lack gAnkB) with WT gAnkB resulted in prominent bundling of microtubules, which did not occur with mutant gAnkB with impaired microtubule-binding activity. Similarly, rescue of gAnkB-deficient neurons with WT gAnkB suppressed axonal branching and invasion of EB3-tagged microtubules into filopodia, which did not occur with the same mutant gAnkB. Together, these findings demonstrate that gAnkB suppresses axon collateral branching and prevents microtubule invasion of nascent axon branches through direct interaction with microtubules.

scholarly journals Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms

2021 ◽  
Vol 22 (2) ◽  
pp. 751
Author(s):  
Min Young Park ◽  
Bala Murali Krishna Vasamsetti ◽  
Wan Seop Kim ◽  
Hee Jung Kang ◽  
Do-Young Kim ◽  
...  
Keyword(s):  
Graft Rejection ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Inflammatory Responses ◽  
Blood Parameters ◽  
Quantitative Real Time Pcr ◽  
Porcine Heart ◽  
End Stage Heart Failure ◽  
End Stage

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey’s blood parameters were analyzed on days −7, −3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.

scholarly journals Regulation of Store-Operated Ca2+ Entry by SARAF

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1887
Author(s):  
Inbal Dagan ◽  
Raz Palty
Keyword(s):  
Molecular Mechanisms ◽  
Feedback Mechanism ◽  
Cellular Biology ◽  
Excitable Cells ◽  
Major Pathway ◽  
Negative Feedback Mechanism ◽  
Crac Channels ◽  
Dependent Inactivation ◽  
Crac Channel ◽  
The One

Calcium (Ca2+) signaling plays a dichotomous role in cellular biology, controlling cell survival and proliferation on the one hand and cellular toxicity and cell death on the other. Store-operated Ca2+ entry (SOCE) by CRAC channels represents a major pathway for Ca2+ entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) and the plasma-membrane Ca2+ channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca2+ flux is regulated by a negative feedback mechanism of slow Ca2+ dependent inactivation (SCDI). The identification of the SOCE-associated regulatory factor (SARAF) and investigations of its role in SCDI have led to new functional and molecular insights into how SOCE is controlled. In this review, we provide an overview of the functional and molecular mechanisms underlying SCDI and discuss how the interaction between SARAF, STIM1, and Orai1 shapes Ca2+ signaling in cells.

scholarly journals Endurance Training Regulates Expression of Some Angiogenesis-Related Genes in Cardiac Tissue of Experimentally Induced Diabetic Rats

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 498
Author(s):  
Mojdeh Khajehlandi ◽  
Lotfali Bolboli ◽  
Marefat Siahkuhian ◽  
Mohammad Rami ◽  
Mohammadreza Tabandeh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endurance Training ◽  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Critical Role ◽  
Diabetic Rats ◽  
Moderate Intensity ◽  
Pcr Analysis ◽  
Cardiac Tissues ◽  
The Impact

Exercise can ameliorate cardiovascular dysfunctions in the diabetes condition, but its precise molecular mechanisms have not been entirely understood. The aim of the present study was to determine the impact of endurance training on expression of angiogenesis-related genes in cardiac tissue of diabetic rats. Thirty adults male Wistar rats were randomly divided into three groups (N = 10) including diabetic training (DT), sedentary diabetes (SD), and sedentary healthy (SH), in which diabetes was induced by a single dose of streptozotocin (50 mg/kg). Endurance training (ET) with moderate-intensity was performed on a motorized treadmill for six weeks. Training duration and treadmill speed were increased during five weeks, but they were kept constant at the final week, and slope was zero at all stages. Real-time polymerase chain reaction (RT-PCR) analysis was used to measure the expression of myocyte enhancer factor-2C (MEF2C), histone deacetylase-4 (HDAC4) and Calmodulin-dependent protein kinase II (CaMKII) in cardiac tissues of the rats. Our results demonstrated that six weeks of ET increased gene expression of MEF2C significantly (p < 0.05), and caused a significant reduction in HDAC4 and CaMKII gene expression in the DT rats compared to the SD rats (p < 0.05). We concluded that moderate-intensity ET could play a critical role in ameliorating cardiovascular dysfunction in a diabetes condition by regulating the expression of some angiogenesis-related genes in cardiac tissues.

scholarly journals Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

2021 ◽  
Vol 22 (7) ◽  
pp. 3513
Author(s):  
Michal Kowara ◽  
Agnieszka Cudnoch-Jedrzejewska
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Cellular Heterogeneity ◽  
Ldl Oxidation ◽  
Plaque Development ◽  
New Directions ◽  
Life Threatening ◽  
Non Coding Rnas ◽  
Cellular Pathways ◽  
Key Aspects

Atherosclerotic plaque is the pathophysiological basis of important and life-threatening diseases such as myocardial infarction. Although key aspects of the process of atherosclerotic plaque development and progression such as local inflammation, LDL oxidation, macrophage activation, and necrotic core formation have already been discovered, many molecular mechanisms affecting this process are still to be revealed. This minireview aims to describe the current directions in research on atherogenesis and to summarize selected studies published in recent years—in particular, studies on novel cellular pathways, epigenetic regulations, the influence of hemodynamic parameters, as well as tissue and microorganism (microbiome) influence on atherosclerotic plaque development. Finally, some new and interesting ideas are proposed (immune cellular heterogeneity, non-coding RNAs, and immunometabolism) which will hopefully bring new discoveries in this area of investigation.

Differential use of SCL/TAL-1 DNA-binding domain in developmental hematopoiesis

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1056-1067 ◽  
Author(s):  
Mira T. Kassouf ◽  
Hedia Chagraoui ◽  
Paresh Vyas ◽  
Catherine Porcher
Keyword(s):  
Dna Binding ◽  
Molecular Mechanisms ◽  
Binding Activity ◽  
Hematopoietic Stem ◽  
Helix Loop Helix ◽  
Experimental Systems ◽  
Dna Binding Activity ◽  
Independent Functions

Abstract Dissecting the molecular mechanisms used by developmental regulators is essential to understand tissue specification/differentiation. SCL/TAL-1 is a basic helix-loop-helix transcription factor absolutely critical for hematopoietic stem/progenitor cell specification and lineage maturation. Using in vitro and forced expression experimental systems, we previously suggested that SCL might have DNA-binding–independent functions. Here, to assess the requirements for SCL DNA-binding activity in vivo, we examined hematopoietic development in mice carrying a germline DNA-binding mutation. Remarkably, in contrast to complete absence of hematopoiesis and early lethality in scl-null embryos, specification of hematopoietic cells occurred in homozygous mutant embryos, indicating that direct DNA binding is dispensable for this process. Lethality was forestalled to later in development, although some mice survived to adulthood. Anemia was documented throughout development and in adulthood. Cellular and molecular studies showed requirements for SCL direct DNA binding in red cell maturation and indicated that scl expression is positively autoregulated in terminally differentiating erythroid cells. Thus, different mechanisms of SCL's action predominate depending on the developmental/cellular context: indirect DNA binding activities and/or sequestration of other nuclear regulators are sufficient in specification processes, whereas direct DNA binding functions with transcriptional autoregulation are critically required in terminal maturation processes.

scholarly journals Titanium dioxide nanoparticles promote arrhythmias via a direct interaction with rat cardiac tissue

2014 ◽  
Vol 11 (1) ◽  
Author(s):  
Monia Savi ◽  
Stefano Rossi ◽  
Leonardo Bocchi ◽  
Laura Gennaccaro ◽  
Francesca Cacciani ◽  
...  
Keyword(s):  
Titanium Dioxide ◽  
Cardiac Tissue ◽  
Titanium Dioxide Nanoparticles ◽  
Direct Interaction

scholarly journals Mammalian and Drosophila cells adhere to the laminin α4 LG4 domain through syndecans, but not glypicans

2004 ◽  
Vol 382 (3) ◽  
pp. 933-943 ◽  
Author(s):  
Hironobu YAMASHITA ◽  
Akira GOTO ◽  
Tatsuhiko KADOWAKI ◽  
Yasuo KITAGAWA
Keyword(s):  
Cell Adhesion ◽  
Umbilical Vein ◽  
Heparan Sulphate ◽  
Direct Interaction ◽  
Binding Activity ◽  
Main Body ◽  
Heparin Binding ◽  
Adhesion Activity ◽  
Umbilical Vein Endothelial Cells

We have previously shown that the LG4 (laminin G-like) domain of the laminin α4 chain is responsible for the significantly higher affinity of the α4 chain to heparin than found for other α chains [Yamaguchi, Yamashita, Mori, Okazaki, Nomizu, Beck and Kitagawa (2000) J. Biol. Chem. 275, 29458–29465]; four basic residues were identified to be essential for this activity [Yamashita, Beck and Kitagawa (2004) J. Mol. Biol. 335, 1145–1149]. By creating GST (glutathione S-transferase)-fused LG1, LG2, LG4 and LG5 proteins, we found that only LG4 is active for the adhesion of human HT1080 cells, human umbilical vein endothelial cells and Drosophila haemocytes Kc167 with a half-saturating concentration of 20 μg/ml. Adhesion was counteracted by treatment of the cells with heparin, heparan sulphate and heparitinase I. Upon mutating the four basic residues essential for heparin binding within LG4, the adhesion activity was abolished. Pull-down experiments using glutathione beads/GST-fusion proteins indicate a direct interaction of LG4 with syndecan-4, which might be the major receptor for cell adhesion. Neither the release of glypican-1 by treating human cells with phosphatidylinositol-specific phospholipase C nor targeted knockdown of dally or dally-like protein impaired the cell-adhesion activity. As the LG4–LG5 domain of the α4 chain is cleaved in vivo from the main body of laminin-8 (α4β1γ1), we suggest that the heparan sulphate proteoglycan-binding activity of LG4 is significant in modulating the signalling of Wnt, Decapentaplegic and fibroblast growth factors.

scholarly journals Calnexin revealed as an ether-a-go-go chaperone by getting mutant worms up and going

2018 ◽  
Vol 150 (8) ◽  
pp. 1059-1061
Author(s):  
Jonathan T. Pierce
Keyword(s):  
Ion Channels ◽  
Dynamic Control ◽  
Cell Types ◽  
K Channel ◽  
Membrane Domains ◽  
Excitable Cells ◽  
Patch Clamp Recording ◽  
Cell Excitability ◽  
Distinct Membrane

The role of ion channels in cell excitability was first revealed in a series of voltage clamp experiments by Hodgkin and Huxley in the 1950s. However, it was not until the 1970s that patch-clamp recording ushered in a revolution that allowed physiologists to witness how ion channels flicker open and closed at angstrom scale and with microsecond resolution. The unexpectedly tight seal made by the patch pipette in the whole-cell configuration later allowed molecular biologists to suck up the insides of identified cells to unveil their unique molecular contents. By refining these techniques, researchers have scrutinized the surface and contents of excitable cells in detail over the past few decades. However, these powerful approaches do not discern which molecules are responsible for the dynamic control of the genesis, abundance, and subcellular localization of ion channels. In this dark territory, teams of unknown and poorly understood molecules guide specific ion channels through translation, folding, and modification, and then they shuttle them toward and away from distinct membrane domains via different subcellular routes. A central challenge in understanding these processes is the likelihood that these diverse regulatory molecules may be specific to ion channel subtypes, cell types, and circumstance. In work described in this issue, Bai et al. (2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812025) begin to shed light on the biogenesis of UNC-103, a K+ channel found in Caenorhabditis elegans.

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