The cardiac type 2 ryanodine receptor (RYR2) is activated by Ca2+-induced Ca2+ release (CICR). The inherent positive feedback of CICR is well controlled in cells, but the nature of this control is debated. Here, we explore how the Ca2+ flux (lumen-to-cytosol) carried by an open RYR2 channel influences its own cytosolic Ca2+ regulatory sites as well as those on a neighboring channel. Both flux-dependent activation and inhibition of single channels were detected when there were super-physiological Ca2+ fluxes (>3 pA). Single-channel results indicate a pore inhibition site distance of 1.2 +/- 0.16 nm and that the activation site on an open channel is shielded/protected from its own flux. Our results indicate that the Ca2+ flux mediated by an open RYR2 channel in cells (approximately 0.5 pA) is too small to substantially regulate (activate or inhibit) the channel carrying it, even though it is sufficient to activate a neighboring RYR2 channel.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806413 | PMC |
| http://dx.doi.org/10.1085/jgp.200910273 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Role of RyR2 Mutations in Congenital Heart Diseases: Insights Into Cardiac Electrophysiological Mechanisms.
J Cardiovasc Electrophysiol
January 2025
Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
Ryanodine receptor 2 (RyR2) protein, a calcium ion release channel in the sarcoplasmic reticulum (SR) of myocardial cells, plays a crucial role in regulating cardiac systolic and diastolic functions. Mutations in RyR2 and its dysfunction are implicated in various congenital heart diseases (CHDs). Studies have shown that mutations in the RYR2 gene, which encodes the RyR2 protein, are linked to several cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), calcium release deficiency syndrome (CRDS), and atrial fibrillation (AF).
View Article and Find Full Text PDFFlecainide Specifically Targets the Monovalent Countercurrent Through the Cardiac Ryanodine Receptor, While a Dominant Opposing Ca/Ba Current Is Present.
Int J Mol Sci
December 2024
Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 840 05 Bratislava, Slovakia.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly arrhythmogenic syndrome triggered by stress, primarily linked to gain-of-function point mutations in the cardiac ryanodine receptor (RyR2). Flecainide, as an effective therapy for CPVT, is a known blocker of the surface-membrane Na channel, also affecting the intracellular RyR2 channel. The therapeutic relevance of the flecainide-RyR2 interaction remains controversial, as flecainide blocks only the RyR2 current flowing in the opposite direction to the physiological Ca release from the sarcoplasmic reticulum (SR).
View Article and Find Full Text PDFDisparate molecular mechanisms in cardiac ryanodine receptor channelopathies.
Front Mol Biosci
December 2024
Swansea University Medical School, Institute of Life Science, Swansea, United Kingdom.
Aims: Mutations in the cardiac ryanodine receptor (RyR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD).
Methods And Results: We consulted the high-resolution RyR2 structure in both open and closed configuration to identify mutations G357S/R407I and A77T, which lie within the NTD intra- and inter-subunit interface with the Core Solenoid (CSol), respectively.
Attempts to Create Transgenic Mice Carrying the Q3924E Mutation in RyR2 Ca Binding Site.
Cells
December 2024
Cardiac Signaling Center, University of South Carolina, Medical University of South Carolina and Clemson University, Charleston, SC 29425, USA.
Over 200 point mutations in the ryanodine receptor (RyR2) of the cardiac sarcoplasmic reticulum (SR) are known to be associated with cardiac arrhythmia. We have already reported on the calcium signaling phenotype of a point mutation in RyR2 Ca binding site Q3925E expressed in human stem-cell-derived cardiomyocytes (hiPSC-CMs) that was found to be lethal in a 9-year-old girl. CRISPR/Cas9-gene-edited mutant cardiomyocytes carrying the RyR2-Q3925E mutation exhibited a loss of calcium-induced calcium release (CICR) and caffeine-triggered calcium release but continued to beat arrhythmically without generating significant SR Ca release, consistent with a remodeling of the calcium signaling pathway.
View Article and Find Full Text PDFUncovering potential causal genes for undiagnosed congenital anomalies using an in-house pipeline for trio-based whole-genome sequencing.
Hum Genomics
January 2025
Division of Genome Science, Department of Precision Medicine, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, Chungbuk, 28159, Republic of Korea.
Background: Congenital anomalies (CAs) encompass a wide spectrum of structural and functional abnormalities during fetal development, commonly presenting at birth. Identifying the cause of CA is essential for accurate diagnosis and treatment. Using a target-gene approach, genetic variants could be found in certain CA patients.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!