226 research outputs found
Ryanodine receptor dysfunction and the resolution revolution: how Nobel Prize-winning techniques transform cardiovascular research
No full textmodels‐towards targeting of complex mechanisms
No full textHeart failure (HF) is a complex disease syndrome, which affects physiology at all levels, from the molecule to the whole organism. Following a causative insult, a maladaptive response occurs, which sustains cardiac remodelling and leads to a final common pathway of debilitating HF symptoms. In terms of mechanisms, distinct defects of excitation-contraction coupling compartments and organelles have been identified in cardiac samples of patients and animal models, which include changes in Ca(2+) transport proteins and T-tubules. From a physiological standpoint, the source of regulatory intracellular Ca(2+) is defined by ∼20,000 Ca(2+) release units per cardiac myocyte, which jointly modulate contractile force production. We and others have characterized key changes in protein and membrane components of Ca(2+) release units during HF in patient samples and transgenic models to gain insight into complex disease mechanisms. While earlier HF studies identified intracellular Ca(2+) release as a major cause of contractile dysfunction, electrical dysfunction has gained attention as an important mechanism of HF mortality. In parallel, high-resolution imaging techniques have become instrumental to understand HF mechanisms in the intact cell and tissue environment, supporting translation of novel diagnostic strategies. Indeed, the increased spatial and temporal resolution of different experimental imaging techniques addresses the vastly different scales of HF pathophysiology, to correlate experimental with clinical surrogate markers, and to extend mechanisms to early, often subtle changes in HF. This last goal, in particular, will be essential to translate novel pathophysiological insight back to the growing number of asymptomatic individuals at increased risk for HF development, who may benefit most from early therapeutic interventions
Cardiac multiscale bioimaging: from nano- through micro- to mesoscales
No full textCardiac multiscale bioimaging is an emerging field that aims to provide a comprehensive understanding of the heart and its functions at various levels, from the molecular to the entire organ. It combines both physiologically and clinically relevant dimensions: from nano- and micrometer resolution imaging based on vibrational spectroscopy and high-resolution microscopy to assess molecular processes in cardiac cells and myocardial tissue, to mesoscale structural investigations to improve the understanding of cardiac (patho)physiology. Tailored super-resolution deep microscopy with advanced proteomic methods and hands-on experience are thus strategically combined to improve the quality of cardiovascular research and support future medical decision-making by gaining additional biomolecular information for translational and diagnostic applications
New Insights into the Proteolytic Regulation of the Structural Protein Junctophilin-2 by Calpain
No full textMultiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia
No full textCatecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1-5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with 'leaky' RyR2
The Role of Junctophilin Proteins in Cellular Function
No full textJunctophilins (JPHs) comprise a family of structural proteins that connect the plasma membrane to intracellular organelles such as the endo/sarcoplasmic reticulum. Tethering of these membrane structures results in the formation of highly organized subcellular junctions that play important signaling roles in all excitable cell types. There are four JPH isoforms, expressed primarily in muscle and neuronal cell types. Each JPH protein consists of 6 'membrane occupation and recognition nexus' (MORN) motifs, a joining region connecting these to another set of 2 MORN motifs, a putative alpha-helical region, a divergent region exhibiting low homology between JPH isoforms, and a carboxy-terminal transmembrane region anchoring into the ER/SR membrane. JPH isoforms play essential roles in developing and maintaining subcellular membrane junctions. Conversely, inherited mutations in JPH2 cause hypertrophic or dilated cardiomyopathy, while trinucleotide expansions in the JPH3 gene cause Huntington Disease-Like 2. Loss of JPH1 protein levels can cause skeletal myopathy, while loss of cardiac JPH2 levels causes heart failure and atrial fibrillation, among other disease. This review will provide a comprehensive overview of the JPH gene family, phylogeny, and evolutionary analysis of JPH genes and other MORN domain proteins. JPH biogenesis, membrane tethering, and binding partners will be discussed, as well as functional roles of JPH isoforms in excitable cells. Finally, potential roles of JPH isoform deficits in human disease pathogenesis will be reviewed
Defective Ryanodine Receptor Interdomain Interactions May Contribute to Intracellular Ca2+ Leak: A Novel Therapeutic Target in Heart Failure
No full text1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities
No full textMitronova GY, Quentin C, Belov VN, Wegener J, Kiszka KA, Lehnart SE. 1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities. Journal of Medicinal Chemistry. 2023
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