LIVIVO - Das Suchportal für Lebenswissenschaften

switch to English language
Zurück zur letzten Suche Suchhistorie
Erweiterte Suche

Ihre letzten Suchen

  1. AU="Mitchell, Colleen C"
  2. AU="Kurbatov, Ilya Y"
  3. AU="Guevara-Álvarez, A"
  4. AU="Barker, Darren"
  5. AU="Muschaweckh, Andreas"
  6. AU="Saibi, Lotfi"
  7. AU=Wagener Jeffrey S AU=Wagener Jeffrey S
  8. AU="Christian Tschuschke"
  9. AU="Gong, Hexiang"
  10. AU="Ziembiec, Nancy A"
  11. AU="Hameed, Safraj Shahul"
  12. AU="Elliott, Alison M"
  13. AU="Nakeshbandi, Mohamed"
  14. AU=Sonthalia Nikhil AU=Sonthalia Nikhil
  15. AU="Kohanbash, Gary" AU="Kohanbash, Gary"
  16. AU=Nawrocki Mariusz J.
  17. AU="Jayme Borensztajn"
  18. AU=Schaerf Raymond H M
  19. AU="Chachar, Aijaz Zeeshan Khan"
  20. AU=Forster H V
  21. AU=Yang G-F
  22. AU="Kaplan, Robert C"
  23. AU="Rood, Julian I."
  24. AU="Manhes, Caroline"
  25. AU="Jacobsen, Cristiane Cavalcanti"
  26. AU="Anja Kukic"
  27. AU="Zhang, N"
  28. AU="Cunningham, Thomas J"
  29. AU="Wu, Y P"
  30. AU="Sumbul, Sabiha"
  31. AU="Razolli, Daniela S"
  32. AU="Asif, Mohsin"
  33. AU="Choudhary, Diksha"
  34. AU="Liu, Yongmei"
  35. AU=Goldshaid Liat
  36. AU="Sandeep Dhayade"
  37. AU="Ashkin, David"
  38. AU="Yukioka, Hideo"
  39. AU="Giles, M"
  40. AU="Keshavarzian, Tina"
  41. AU="Richard Holtmeier"
  42. AU=Sanborn Keri B
  43. AU=Crestani Larissa AU=Crestani Larissa
  44. AU=Nassiri Amir Ahmad
  45. AU="Keiser, Olivia"
  46. AU="Scholz, Martin"
  47. AU="Vassilis Pigadas" AU="Vassilis Pigadas"
  48. AU="Schlievert, Patrick M"
  49. AU=Egan Katie G
  50. AU="Benzadón, Mariano"
  51. AU="Truong, Thérèse"
  52. AU="de Oliveira, Aline Lima"
  53. AU="Lehto, Sonya G"
  54. AU="Simi Jacob"
  55. AU="Shipman, Michael"
  56. AU=Pons Linda
  57. AU="Notoya, A"
  58. AU="Williams, Olajide A"
  59. AU=Errington Jeff
  60. AU="Tortolani, Christina C"
  61. AU="Patel, Jenil R"
  62. AU="Aires, Rafaela"
  63. AU="Habibelahi, Abbas"
  64. AU="Temes, Javier"
  65. AU="Miwa, Toru"
  66. AU="Jaller, Elvira"
  67. AU="Manso Sanchez, L M"

Suchergebnis

Treffer 1 - 7 von insgesamt 7

Suchoptionen

  1. Artikel ; Online: A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1.

    Riley, Mitchell J / Mitchell, Colleen C / Ernst, Sarah E / Taylor, Eric B / Welsh, Michael J

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Band 121, Heft 9, Seite(n) e2318956121

    Abstract: The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy ... ...

    Abstract The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.
    Mesh-Begriff(e) Humans ; Animals ; Phosphoglycerate Kinase/metabolism ; Prazosin/pharmacology ; Prazosin/analogs & derivatives ; Parkinson Disease/drug therapy ; Glycolysis
    Chemische Substanzen Terazosin (8L5014XET7) ; Phosphoglycerate Kinase (EC 2.7.2.3) ; Prazosin (XM03YJ541D)
    Sprache Englisch
    Erscheinungsdatum 2024-02-20
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2318956121
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Zusatzmaterialien

    Kategorien

    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 1148: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Über subito bestellen

    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

  2. Artikel ; Online: A computational investigation of cardiac caveolae as a source of persistent sodium current.

    Besse, Ian M / Mitchell, Colleen C / Hund, Thomas J / Shibata, Erwin F

    Frontiers in physiology

    2011  Band 2, Seite(n) 87

    Abstract: Recent studies of cholesterol-rich membrane microdomains, called caveolae, reveal that caveolae are reservoirs of "recruitable" sodium ion channels. Caveolar channels constitute a substantial and previously unrecognized source of sodium current in ... ...

    Abstract Recent studies of cholesterol-rich membrane microdomains, called caveolae, reveal that caveolae are reservoirs of "recruitable" sodium ion channels. Caveolar channels constitute a substantial and previously unrecognized source of sodium current in cardiac cells. In this paper we model for the first time caveolar sodium currents and their contributions to cardiac action potential morphology. We show that the β-agonist-induced opening of caveolae may have substantial impacts on peak overshoot, maximum upstroke velocity, and ultimately conduction velocity. Additionally, we show that prolonged action potentials and the formation of potentially arrhythmogenic afterdepolarizations, can arise if caveolae open intermittently throughout the action potential. Our simulations suggest that caveolar sodium current may constitute a route, which is independent of channelopathies, to delayed repolarization and the arrhythmias associated with such delays.
    Sprache Englisch
    Erscheinungsdatum 2011-11-30
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X ; 1664-042X
    ISSN (online) 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2011.00087
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Zusatzmaterialien

    Kategorien

    Über subito bestellen

    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

  3. Artikel: A two-current model for the dynamics of cardiac membrane.

    Mitchell, Colleen C / Schaeffer, David G

    Bulletin of mathematical biology

    2003  Band 65, Heft 5, Seite(n) 767–793

    Abstract: In this paper we introduce and study a model for electrical activity of cardiac membrane which incorporates only an inward and an outward current. This model is useful for three reasons: (1) Its simplicity, comparable to the FitzHugh-Nagumo model, makes ... ...

    Abstract In this paper we introduce and study a model for electrical activity of cardiac membrane which incorporates only an inward and an outward current. This model is useful for three reasons: (1) Its simplicity, comparable to the FitzHugh-Nagumo model, makes it useful in numerical simulations, especially in two or three spatial dimensions where numerical efficiency is so important. (2) It can be understood analytically without recourse to numerical simulations. This allows us to determine rather completely how the parameters in the model affect its behavior which in turn provides insight into the effects of the many parameters in more realistic models. (3) It naturally gives rise to a one-dimensional map which specifies the action potential duration as a function of the previous diastolic interval. For certain parameter values, this map exhibits a new phenomenon--subcritical alternans--that does not occur for the commonly used exponential map.
    Mesh-Begriff(e) Action Potentials ; Cell Membrane/physiology ; Computer Simulation ; Electrophysiology ; Heart Conduction System/physiology ; Humans ; Models, Cardiovascular ; Myocytes, Cardiac/physiology ; Numerical Analysis, Computer-Assisted
    Sprache Englisch
    Erscheinungsdatum 2003-09
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 184905-0
    ISSN 1522-9602 ; 0092-8240 ; 0007-4985
    ISSN (online) 1522-9602
    ISSN 0092-8240 ; 0007-4985
    DOI 10.1016/S0092-8240(03)00041-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Volltext online

    Zusatzmaterialien

    Kategorien

    Verfügbar in ZB MED Köln/Königswinter

    Zs.B 754: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Über subito bestellen

    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

  4. Artikel ; Online: Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome.

    Wolf, Roseanne M / Mitchell, Colleen C / Christensen, Matthew D / Mohler, Peter J / Hund, Thomas J

    American journal of physiology. Heart and circulatory physiology

    2010  Band 299, Heft 5, Seite(n) H1505–14

    Abstract: Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum. Ion channel dysfunction due to congenital or acquired defects has been ...

    Abstract Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum. Ion channel dysfunction due to congenital or acquired defects has been linked to human cardiac arrhythmia. More recently, defects in ion channel-associated proteins have been associated with arrhythmia. Ankyrin-B is a multifunctional adapter protein responsible for targeting select ion channels, transporters, cytoskeletal proteins, and signaling molecules in excitable cells, including neurons, pancreatic β-cells, and cardiomyocytes. Ankyrin-B dysfunction has been linked to cardiac arrhythmia in human patients and ankyrin-B heterozygous (ankyrin-B(+/-)) mice with a phenotype characterized by sinus node dysfunction, susceptibility to ventricular arrhythmias, and sudden death ("ankyrin-B syndrome"). At the cellular level, ankyrin-B(+/-) cells have defects in the expression and membrane localization of the Na(+)/Ca(2+) exchanger and Na(+)-K(+)-ATPase, Ca(2+) overload, and frequent afterdepolarizations, which likely serve as triggers for lethal cardiac arrhythmias. Despite knowledge gathered from mouse models and human patients, the molecular mechanism responsible for cardiac arrhythmias in the setting of ankyrin-B dysfunction remains unclear. Here, we use mathematical modeling to provide new insights into the cellular pathways responsible for Ca(2+) overload and afterdepolarizations in ankyrin-B(+/-) cells. We show that the Na(+)/Ca(2+) exchanger and Na(+)-K(+)-ATPase play related, yet distinct, roles in intracellular Ca(2+) accumulation, sarcoplasmic reticulum Ca(2+) overload, and afterdepolarization generation in ankyrin-B(+/-) cells. These findings provide important insights into the molecular mechanisms underlying a human disease and are relevant for acquired human arrhythmia, where ankyrin-B dysfunction has recently been identified.
    Mesh-Begriff(e) Animals ; Ankyrins/deficiency ; Ankyrins/genetics ; Ankyrins/metabolism ; Calcium/metabolism ; Computer Simulation ; Death, Sudden, Cardiac ; Disease Models, Animal ; Humans ; Mice ; Models, Theoretical ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Sick Sinus Syndrome/genetics ; Sick Sinus Syndrome/metabolism ; Sick Sinus Syndrome/physiopathology ; Sodium-Calcium Exchanger/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Syndrome ; Ventricular Fibrillation/genetics ; Ventricular Fibrillation/metabolism ; Ventricular Fibrillation/physiopathology
    Chemische Substanzen ANK2 protein, human ; Ankyrins ; Sodium-Calcium Exchanger ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13) ; Calcium (SY7Q814VUP)
    Sprache Englisch
    Erscheinungsdatum 2010-08-20
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 603838-4
    ISSN 1522-1539 ; 0363-6135
    ISSN (online) 1522-1539
    ISSN 0363-6135
    DOI 10.1152/ajpheart.00503.2010
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Zusatzmaterialien

    Kategorien

    Verfügbar in ZB MED Köln/Königswinter

    Uc I Zs.89: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Über subito bestellen

    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

  5. Artikel ; Online: Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis.

    Wolf, Roseanne M / Glynn, Patric / Hashemi, Seyed / Zarei, Keyan / Mitchell, Colleen C / Anderson, Mark E / Mohler, Peter J / Hund, Thomas J

    American journal of physiology. Heart and circulatory physiology

    2013  Band 304, Heft 9, Seite(n) H1253–66

    Abstract: 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 ... ...

    Abstract 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 Ca(2+) 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(+)/Ca(2+) 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.
    Mesh-Begriff(e) Action Potentials ; Animals ; Ankyrins/metabolism ; Arrhythmias, Cardiac/physiopathology ; Atrial Fibrillation/physiopathology ; Calcium Channels, L-Type/metabolism ; Computer Simulation ; Fibrosis/physiopathology ; Heart Atria/pathology ; Humans ; Mice ; Models, Cardiovascular ; Sinoatrial Node/pathology ; Sinoatrial Node/physiopathology ; Sodium-Calcium Exchanger/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism
    Chemische Substanzen Ank2 protein, mouse ; Ankyrins ; CACNA1D protein, human ; Calcium Channels, L-Type ; Sodium-Calcium Exchanger ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13)
    Sprache Englisch
    Erscheinungsdatum 2013-02-22
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 603838-4
    ISSN 1522-1539 ; 0363-6135
    ISSN (online) 1522-1539
    ISSN 0363-6135
    DOI 10.1152/ajpheart.00734.2012
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Zusatzmaterialien

    Kategorien

    Verfügbar in ZB MED Köln/Königswinter

    Uc I Zs.89: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Über subito bestellen

    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

  6. Artikel: Precision of neural timing: effects of convergence and time-windowing.

    Reed, Michael C / Blum, Jacob J / Mitchell, Colleen C

    Journal of computational neuroscience

    2002  Band 13, Heft 1, Seite(n) 35–47

    Abstract: We study the improvement in timing accuracy in a neural system having n identical input neurons projecting to one target neuron. The n input neurons receive the same stimulus but fire at stochastic times selected from one of four specified probability ... ...

    Abstract We study the improvement in timing accuracy in a neural system having n identical input neurons projecting to one target neuron. The n input neurons receive the same stimulus but fire at stochastic times selected from one of four specified probability densities, f, each with standard deviation 1.0 msec. The target cell fires if and when it receives m inputs within a time window of epsilon msec. Let sigma(n,m,epsilon) denote the standard deviation of the time of firing of the target neuron (i.e. the standard deviation of the target neuron's latency relative to the arrival time of the stimulus). Mathematical analysis shows that sigma(n,m,epsilon) is a very complicated function of n, m, and epsilon. Typically, sigma(n,m,epsilon) is a non-monotone function of m and epsilon and the improvement of timing accuracy is highly dependent of the shape of the probability density for the time of firing of the input neurons. For appropriate choices of m, epsilon, and f, the standard deviation sigma(n,m,epsilon) may be as low as 1/n. Thus, depending on these variables, remarkable improvements in timing accuracy of such a stochastic system may occur.
    Mesh-Begriff(e) Animals ; Electrophysiology ; Models, Neurological ; Nervous System Physiological Phenomena ; Neurons/physiology ; Probability ; Reaction Time/physiology ; Stochastic Processes
    Sprache Englisch
    Erscheinungsdatum 2002-06-21
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1230659-9
    ISSN 1573-6873 ; 0929-5313
    ISSN (online) 1573-6873
    ISSN 0929-5313
    DOI 10.1023/a:1019692310817
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Volltext online

    Zusatzmaterialien

    Kategorien

    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 4250: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Über subito bestellen

    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

  7. Artikel ; Online: Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease.

    Koval, Olha M / Snyder, Jedidiah S / Wolf, Roseanne M / Pavlovicz, Ryan E / Glynn, Patric / Curran, Jerry / Leymaster, Nicholas D / Dun, Wen / Wright, Patrick J / Cardona, Natalia / Qian, Lan / Mitchell, Colleen C / Boyden, Penelope A / Binkley, Philip F / Li, Chenglong / Anderson, Mark E / Mohler, Peter J / Hund, Thomas J

    Circulation

    2012  Band 126, Heft 17, Seite(n) 2084–2094

    Abstract: Background: Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a ... ...

    Abstract Background: Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated.
    Methods and results: We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium.
    Conclusions: We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.
    Mesh-Begriff(e) Animals ; Arrhythmias, Cardiac/enzymology ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/physiology ; Cells, Cultured ; Cytoplasm/enzymology ; Cytoplasm/genetics ; Cytoplasm/metabolism ; Dogs ; Genetic Variation ; HEK293 Cells ; Humans ; Mice ; NAV1.5 Voltage-Gated Sodium Channel/genetics ; NAV1.5 Voltage-Gated Sodium Channel/metabolism ; Phosphorylation ; Protein Processing, Post-Translational/genetics
    Chemische Substanzen NAV1.5 Voltage-Gated Sodium Channel ; SCN5A protein, human ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17)
    Sprache Englisch
    Erscheinungsdatum 2012-09-24
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80099-5
    ISSN 1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
    ISSN (online) 1524-4539
    ISSN 0009-7322 ; 0069-4193 ; 0065-8499
    DOI 10.1161/CIRCULATIONAHA.112.105320
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Zusatzmaterialien

    Kategorien

    Verfügbar in ZB MED Köln/Königswinter

    Ui IV Zs.60: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Über subito bestellen

    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

Zum Seitenanfang