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Nernst-Planck-Gaussian finite element modelling of Ca electrodiffusion in amphibian striated muscle transverse tubule-sarcoplasmic reticular triadic junctional domains.
Front Physiol
December 2024
Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom.
Introduction: Intracellular Ca signalling regulates membrane permeabilities, enzyme activity, and gene transcription amongst other functions. Large transmembrane Ca electrochemical gradients and low diffusibility between cell compartments potentially generate short-lived, localised, high-[Ca] microdomains. The highest concentration domains likely form between closely apposed membranes, as at amphibian skeletal muscle transverse tubule-sarcoplasmic reticular (T-SR, triad) junctions.
View Article and Find Full Text PDFUsing a Failing Human Ventricular Cardiomyocyte Model to Re-Evaluate Ca Cycling, Voltage Dependence, and Spark Characteristics.
Biomolecules
October 2024
School of Systems Biology, George Mason University, Fairfax, VA 22030, USA.
Previous studies have observed alterations in excitation-contraction (EC) coupling during end-stage heart failure that include action potential and calcium (Ca) transient prolongation and a reduction of the Ca transient amplitude. Underlying these phenomena are the downregulation of potassium (K) currents, downregulation of the sarcoplasmic reticulum Ca ATPase (SERCA), increase Ca sensitivity of the ryanodine receptor, and the upregulation of the sodium-calcium (Na-Ca) exchanger. However, in human heart failure (HF), debate continues about the relative contributions of the changes in calcium handling vs.
View Article and Find Full Text PDFS100A1ct: A Synthetic Peptide Derived From S100A1 Protein Improves Cardiac Performance and Survival in Preclinical Heart Failure Models.
Circulation
November 2024
Molecular and Translational Cardiology, Heidelberg University Hospital (UKHD), Germany. (D.K., J.R., K.S., K.V., J.B., M.E., A.J., C.B., M.B., P.M.).
Background: The EF-hand Ca sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca ATPase) and RyR2 (ryanodine receptor 2) in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal α-helix (residues 75-94). We hypothesized that a synthetic peptide consisting of residues 75 through 94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance-enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts.
View Article and Find Full Text PDFRole of ryanodine receptor cooperativity in Ca-wave-mediated triggered activity in cardiomyocytes.
J Physiol
December 2024
Physics Department and Center for Interdisciplinary Research in Complex Systems, Northeastern University, Boston, MA, USA.
Ca waves are known to trigger delayed after-depolarizations that can cause malignant cardiac arrhythmias. However, modelling Ca waves using physiologically realistic models has remained a major challenge. Existing models with low Ca sensitivity of ryanodine receptors (RyRs) necessitate large release currents, leading to an unrealistically large Ca transient amplitude incompatible with the experimental observations.
View Article and Find Full Text PDFElectrophysical cardiac remodeling at the molecular level: Insights into ryanodine receptor activation and calcium-induced calcium release from a stochastic explicit-particle model.
Biophys J
November 2024
Computational Neurobiology Lab, The Salk Institute of Biological Studies, La Jolla, California; Department of Chemistry and Biochemistry, The University of California San Diego, La Jolla, California. Electronic address:
We present the first-ever, fully discrete, stochastic model of triggered cardiac Ca dynamics. Using anatomically accurate subcellular cardiac myocyte geometries, we simulate the molecular players involved in Ca handling using high-resolution stochastic and explicit-particle methods at the level of an individual cardiac dyadic junction. Integrating data from multiple experimental sources, the model not only replicates the findings of traditional in silico studies and complements in vitro experimental data but also reveals new insights into the molecular mechanisms driving cardiac dysfunction under stress and disease conditions.
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