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The Journal of General Physiology Sep 2022Flecainide, a cardiac class 1C blocker of the surface membrane sodium channel (NaV1.5), has also been reported to reduce cardiac ryanodine receptor (RyR2)-mediated...
Flecainide, a cardiac class 1C blocker of the surface membrane sodium channel (NaV1.5), has also been reported to reduce cardiac ryanodine receptor (RyR2)-mediated sarcoplasmic reticulum (SR) Ca2+ release. It has been introduced as a clinical antiarrhythmic agent for catecholaminergic polymorphic ventricular tachycardia (CPVT), a condition most commonly associated with gain-of-function RyR2 mutations. Current debate concerns both cellular mechanisms of its antiarrhythmic action and molecular mechanisms of its RyR2 actions. At the cellular level, it targets NaV1.5, RyR2, Na+/Ca2+ exchange (NCX), and additional proteins involved in excitation-contraction (EC) coupling and potentially contribute to the CPVT phenotype. This Viewpoint primarily addresses the various direct molecular actions of flecainide on isolated RyR2 channels in artificial lipid bilayers. Such studies demonstrate different, multifarious, flecainide binding sites on RyR2, with voltage-dependent binding in the channel pore or voltage-independent binding at distant peripheral sites. In contrast to its single NaV1.5 pore binding site, flecainide may bind to at least four separate inhibitory sites on RyR2 and one activation site. None of these binding sites have been specifically located in the linear RyR2 sequence or high-resolution structure. Furthermore, it is not clear which of the inhibitory sites contribute to flecainide's reduction of spontaneous Ca2+ release in cellular studies. A confounding observation is that flecainide binding to voltage-dependent inhibition sites reduces cation fluxes in a direction opposite to physiological Ca2+ flow from SR lumen to cytosol. This may suggest that, rather than directly blocking Ca2+ efflux, flecainide can reduce Ca2+ efflux by blocking counter currents through the pore which otherwise limit SR membrane potential change during systolic Ca2+ efflux. In summary, the antiarrhythmic effects of flecainide in CPVT seem to involve multiple components of EC coupling and multiple actions on RyR2. Their clarification may identify novel specific drug targets and facilitate flecainide's clinical utilization in CPVT.
Topics: Anti-Arrhythmia Agents; Calcium; Flecainide; Humans; Myocytes, Cardiac; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sodium; Tachycardia, Ventricular
PubMed: 35713932
DOI: 10.1085/jgp.202213089 -
Current Alzheimer Research 2020Pathologic calcium (Ca2+) signaling linked to Alzheimer's Disease (AD) involves the intracellular Ca2+ release channels/ryanodine receptors (RyRs). RyRs are... (Review)
Review
Pathologic calcium (Ca2+) signaling linked to Alzheimer's Disease (AD) involves the intracellular Ca2+ release channels/ryanodine receptors (RyRs). RyRs are macromolecular complexes where the protein-protein interactions between RyRs and several regulatory proteins impact the channel function. Pharmacological and genetic approaches link the destabilization of RyRs macromolecular complexes to several human pathologies including brain disorders. In this review, we discuss our recent data, which demonstrated that enhanced neuronal RyR2-mediated Ca2+ leak in AD is associated with posttranslational modifications (hyperphosphorylation, oxidation, and nitrosylation) leading to RyR2 macromolecular complex remodeling, and dissociation of the stabilizing protein Calstabin2 from the channel. We describe RyR macromolecular complex structure and discuss the molecular mechanisms and signaling cascade underlying neuronal RyR2 remodeling in AD. We provide evidence linking RyR2 dysfunction with β-adrenergic signaling cascade that is altered in AD. RyR2 remodeling in AD leads to histopathological lesions, alteration of synaptic plasticity, learning and memory deficits. Targeting RyR macromolecular complex remodeling should be considered as a new therapeutic window to treat/or prevent AD setting and/or progression.
Topics: Alzheimer Disease; Animals; Calcium Channel Blockers; Calcium Signaling; Drug Delivery Systems; Humans; Protein Processing, Post-Translational; Ryanodine Receptor Calcium Release Channel
PubMed: 32096743
DOI: 10.2174/1567205017666200225102941 -
Cell Death & Disease Nov 2021The regulation of intracellular calcium (Ca) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest... (Review)
Review
The regulation of intracellular calcium (Ca) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients' cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient's genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.
Topics: Animals; Disease; Humans; Induced Pluripotent Stem Cells; Models, Biological; Multiple Organ Failure; Mutation; Ryanodine Receptor Calcium Release Channel
PubMed: 34725342
DOI: 10.1038/s41419-021-04337-9 -
Current Pharmaceutical Design 2022RyR1-related myopathies are a family of genetic neuromuscular diseases due to mutations in the RYR1 gene. No treatment exists for any of these myopathies today, which... (Review)
Review
RyR1-related myopathies are a family of genetic neuromuscular diseases due to mutations in the RYR1 gene. No treatment exists for any of these myopathies today, which could change in the coming years with the growing number of studies dedicated to the pre-clinical assessment of various approaches, from pharmacological to gene therapy strategies, using the numerous models developed up to now. In addition, the first clinical trials for these rare diseases have just been completed or are being launched. We review the most recent results obtained for the treatment of RyR1-related myopathies, and, in view of the progress in therapeutic development for other myopathies, we discuss the possible future therapeutic perspectives for RyR1-related myopathies.
Topics: Humans; Muscle, Skeletal; Muscular Diseases; Mutation; Ryanodine Receptor Calcium Release Channel
PubMed: 34514983
DOI: 10.2174/1389201022666210910102516 -
Pflugers Archiv : European Journal of... Dec 2020Many proteins are phosphorylated at more than one phosphorylation site to achieve precise tuning of protein function and/or integrate a multitude of signals into the... (Review)
Review
Many proteins are phosphorylated at more than one phosphorylation site to achieve precise tuning of protein function and/or integrate a multitude of signals into the activity of one protein. Increasing the number of phosphorylation sites significantly broadens the complexity of molecular mechanisms involved in processing multiple phosphorylation sites by one or more distinct kinases. The cardiac ryanodine receptor (RYR2) is a well-established multiple phospho-target of kinases activated in response to β-adrenergic stimulation because this Ca channel is a critical component of Ca handling machinery which is responsible for β-adrenergic enhancement of cardiac contractility. Our review presents a selective overview of the extensive, often conflicting, literature which focuses on identifying reliable lines of evidence to establish if multiple RYR2 phosphorylation is achieved randomly or in a specific sequence, and whether phosphorylation at individual sites is functionally specific and additive or similar and can therefore be substituted.
Topics: Action Potentials; Amino Acid Motifs; Animals; Humans; Myocytes, Cardiac; Phosphorylation; Ryanodine Receptor Calcium Release Channel
PubMed: 33078311
DOI: 10.1007/s00424-020-02473-3 -
Advances in Experimental Medicine and... 2020Ca signals are probably the most common intracellular signaling cellular events, controlling an extensive range of responses in virtually all cells. Many cellular... (Review)
Review
Ca signals are probably the most common intracellular signaling cellular events, controlling an extensive range of responses in virtually all cells. Many cellular stimuli, often acting at cell surface receptors, evoke Ca signals by mobilizing Ca from intracellular stores. Inositol trisphosphate (IP) was the first messenger shown to link events at the plasma membrane to release Ca from the endoplasmic reticulum (ER), through the activation of IP-gated Ca release channels (IP receptors). Subsequently, two additional Ca mobilizing messengers were discovered, cADPR and NAADP. Both are metabolites of pyridine nucleotides, and may be produced by the same class of enzymes, ADP-ribosyl cyclases, such as CD38. Whilst cADPR mobilizes Ca from the ER by activation of ryanodine receptors (RyRs), NAADP releases Ca from acidic stores by a mechanism involving the activation of two pore channels (TPCs). In addition, other pyridine nucleotides have emerged as intracellular messengers. ADP-ribose and 2'-deoxy-ADPR both activate TRPM2 channels which are expressed at the plasma membrane and in lysosomes.
Topics: Animals; Calcium; Calcium Signaling; Cyclic ADP-Ribose; Endoplasmic Reticulum; Humans; Intracellular Space; NADP; Pyridines; Ryanodine Receptor Calcium Release Channel
PubMed: 31646518
DOI: 10.1007/978-3-030-12457-1_15 -
Molecules (Basel, Switzerland) Sep 2020Cardiac arrhythmias are serious, life-threatening diseases associated with the dysregulation of Ca2+ influx into the cytoplasm of cardiomyocytes. This dysregulation... (Review)
Review
Cardiac arrhythmias are serious, life-threatening diseases associated with the dysregulation of Ca2+ influx into the cytoplasm of cardiomyocytes. This dysregulation often arises from dysfunction of ryanodine receptor 2 (RyR2), the principal Ca2+ release channel. Dysfunction of RyR1, the skeletal muscle isoform, also results in less severe, but also potentially life-threatening syndromes. The and genes have been found to harbor three main mutation "hot spots", where mutations change the channel structure, its interdomain interface properties, its interactions with its binding partners, or its dynamics. In all cases, the result is a defective release of Ca2+ ions from the sarcoplasmic reticulum into the myocyte cytoplasm. Here, we provide an overview of the most frequent diseases resulting from mutations to RyR1 and RyR2, briefly review some of the recent experimental structural work on these two molecules, detail some of the computational work describing their dynamics, and summarize the known changes to the structure and function of these receptors with particular emphasis on their N-terminal, central, and channel domains.
Topics: Humans; Models, Molecular; Muscular Diseases; Protein Domains; Protein Isoforms; Ryanodine Receptor Calcium Release Channel; Structure-Activity Relationship
PubMed: 32899693
DOI: 10.3390/molecules25184040 -
Europace : European Pacing,... Mar 2022
Topics: Humans; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 34850886
DOI: 10.1093/europace/euab283 -
American Journal of Physiology. Heart... Sep 2019In the current study, the potential contributions of ryanodine receptors (RyRs) to intrinsic pumping and responsiveness to substance P (SP) were investigated in isolated...
In the current study, the potential contributions of ryanodine receptors (RyRs) to intrinsic pumping and responsiveness to substance P (SP) were investigated in isolated rat mesenteric collecting lymphatic vessels. Responses to SP were characterized in lymphatic vessels in the absence or presence of pretreatment with nifedipine to block L-type Ca channels, caffeine to block normal release and uptake of Ca from the sarcoplasmic reticulum, ryanodine to block all RyR isoforms, or dantrolene to more selectively block RyR1 and RyR3. RyR expression and localization in lymphatics was also assessed by quantitative PCR and immunofluorescence confocal microscopy. The results show that SP normally elicits a significant increase in contraction frequency and a decrease in end-diastolic diameter. In the presence of nifedipine, phasic contractions stop, yet subsequent SP treatment still elicits a strong tonic contraction. Caffeine treatment gradually relaxes lymphatics, causing a loss of phasic contractions, and prevents subsequent SP-induced tonic contraction. Ryanodine also gradually diminishes phasic contractions but without causing vessel relaxation and significantly inhibits the SP-induced tonic contraction. Dantrolene treatment did not significantly impair lymphatic contractions nor the response to SP. The mRNA for all RyR isoforms is detectable in isolated lymphatics. RyR2 and RyR3 proteins are found predominantly in the collecting lymphatic smooth muscle layer. Collectively, the data suggest that SP-induced tonic contraction requires both extracellular Ca plus Ca release from internal stores and that RyRs play a role in the normal contractions and responsiveness to SP of rat mesenteric collecting lymphatics. The mechanisms that govern contractions of lymphatic vessels remain unclear. Tonic contraction of lymphatic vessels caused by substance P was blocked by caffeine, which prevents normal uptake and release of Ca from internal stores, but not nifedipine, which blocks L-type channel-mediated Ca entry. Ryanodine, which also disrupts normal sarcoplasmic reticulum Ca release and reuptake, significantly inhibited substance P-induced tonic contraction. Ryanodine receptors 2 and 3 were detected within the smooth muscle layer of collecting lymphatic vessels.
Topics: Animals; Caffeine; Calcium Signaling; Lymphatic Vessels; Male; Mesentery; Muscle Contraction; Muscle, Smooth; Rats, Sprague-Dawley; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Substance P
PubMed: 31274355
DOI: 10.1152/ajpheart.00564.2018 -
Antiviral Research Mar 2021While muscle fatigue, pain and weakness are common co-morbidities in HIV-1 infected people, their underlying cause remain poorly defined. To this end, we evaluated...
While muscle fatigue, pain and weakness are common co-morbidities in HIV-1 infected people, their underlying cause remain poorly defined. To this end, we evaluated whether the common antiretroviral drugs efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) could be a contributing factor by pertubating sarcoplasmic reticulum (SR) Ca cycling. In live-cell imaging, EFV (6.0 μM), ATV (6.0 μM), and RTV (3.0 μM) elicited Ca transients and blebbing of the plasma membranes of C2C12 skeletal muscle myotubes. Pretreating C2C12 skeletal muscle myotubes with the SR Ca release channel blocker ryanodine (50 μM), slowed the rate and amplitude of Ca release from and reuptake of Ca into the SR. EFV, ATV and RTV (1 nM - 20 μM) potentiated and then displaced [H] ryanodine binding to rabbit skeletal muscle ryanodine receptor Ca release channel (RyR1). These drugs at concentrations 0.25-31.2 μM also increased and or decreased the open probability of RyR1 by altering its gating and conductance. ATV (≤5 μM) potentiated and >5μM inhibited the ability of sarco (endo)plasmic reticulum Ca-ATPase (SERCA1) to hydrolyze ATP and transport Ca. RTV (2.5-31.5 μM) dose-dependently inhibited SERCA1-mediated, ATP-dependent Ca transport. EFV (0.25-31.5 μM) had no measurable effect on SERCA1's ability to hydrolyze ATP and transport Ca. These data support the notion that EFV, ATV and RTV could be contributing to skeletal muscle co-morbidities in PLWH by modulating SR Ca homeostasis.
Topics: Alkynes; Animals; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Calcium; Cell Line; Cyclopropanes; Homeostasis; Mice; Muscle, Skeletal; Myoblasts; Rabbits; Ritonavir; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Time-Lapse Imaging
PubMed: 33450312
DOI: 10.1016/j.antiviral.2020.104975