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Neuromuscular Disorders : NMD Oct 2023Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in...
Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.
Topics: Animals; Humans; Acute Disease; Calcium; Malignant Hyperthermia; Mutation; Pancreatitis; Ryanodine Receptor Calcium Release Channel
PubMed: 37783627
DOI: 10.1016/j.nmd.2023.09.003 -
Cell Calcium Jun 2022Ca signalling is of prime importance in controlling numerous cell functions in the brain. Endolysosomes are acidic organelles currently emerging as important Ca stores... (Review)
Review
Ca signalling is of prime importance in controlling numerous cell functions in the brain. Endolysosomes are acidic organelles currently emerging as important Ca stores in astrocytes, microglia, endothelial cells, and neurons. In neurons, these acidic Ca stores are found in axons, soma, dendrites, and axon endings and could provide local sources of Ca to control synaptic transmission, neuronal plasticity, and autophagy to name a few. This review will address how acidic Ca stores are recruited in response to cell stimulation. We will focus on the role of the endolysosomal two-pore channels (TPCs) and their physiological agonist nicotinic acid adenine dinucleotide phosphate (NAADP) and how they interact with cyclic ADP-ribose and ryanodine receptors from the endoplasmic reticulum. Finally, this review will describe new pharmacological tools and animal mutant models now available to explore acidic Ca stores as key elements in brain function and dysfunction.
Topics: Animals; Calcium; Calcium Signaling; Endoplasmic Reticulum; Endothelial Cells; NADP; Ryanodine Receptor Calcium Release Channel
PubMed: 35462080
DOI: 10.1016/j.ceca.2022.102582 -
Nature Communications Jun 2024Calmodulin transduces [Ca] information regulating the rhythmic Ca cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac...
Calmodulin transduces [Ca] information regulating the rhythmic Ca cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac and skeletal muscle. However, the structural dynamics by which calmodulin modulates the sarcoplasmic reticulum Ca release channel, the ryanodine receptor, at physiologically relevant [Ca] is unknown. Using fluorescence lifetime FRET, we resolve different structural states of calmodulin and Ca-driven shifts in the conformation of calmodulin bound to ryanodine receptor. Skeletal and cardiac ryanodine receptor isoforms show different calmodulin-ryanodine receptor conformations, as well as binding and structural kinetics with 0.2-ms resolution, which reflect different functional roles of calmodulin. These FRET methods provide insight into the physiological calmodulin-ryanodine receptor structural states, revealing additional distinct structural states that complement cryo-EM models that are based on less physiological conditions. This technology will drive future studies on pathological calmodulin-ryanodine receptor interactions and dynamics with other important ryanodine receptor bound modulators.
Topics: Ryanodine Receptor Calcium Release Channel; Calmodulin; Calcium; Myocardium; Kinetics; Animals; Muscle, Skeletal; Fluorescence Resonance Energy Transfer; Humans; Protein Conformation; Protein Binding; Sarcoplasmic Reticulum
PubMed: 38879623
DOI: 10.1038/s41467-024-48951-5 -
Cellular Signalling Feb 2022Reversible phosphorylation of ion channels and calcium-handling proteins provides precise post-translational regulation of cardiac excitation and contractility.... (Review)
Review
Reversible phosphorylation of ion channels and calcium-handling proteins provides precise post-translational regulation of cardiac excitation and contractility. Serine/threonine phosphatases govern dephosphorylation of the majority of cardiac proteins. Accordingly, dysfunction of this regulation contributes to the development and progression of heart failure and atrial fibrillation. On the molecular level, these changes include alterations in the expression level and phosphorylation status of Ca handling and excitation-contraction coupling proteins provoked by dysregulation of phosphatases. The serine/threonine protein phosphatase PP1 is one a major player in the regulation of cardiac excitation-contraction coupling. PP1 essentially impacts on cardiac physiology and pathophysiology via interactions with the cardiac ion channels Cav1.2, NKA, NCX and KCNQ1, sarcoplasmic reticulum-bound Ca handling proteins such as RyR2, SERCA and PLB as well as the contractile proteins MLC2, TnI and MyBP-C. PP1 itself but also PP1-regulatory proteins like inhibitor-1, inhibitor-2 and heat-shock protein 20 are dysregulated in cardiac disease. Therefore, they represent interesting targets to gain more insights in heart pathophysiology and to identify new treatment strategies for patients with heart failure or atrial fibrillation. We describe the genetic and holoenzymatic structure of PP1 and review its role in the heart and cardiac disease. Finally, we highlight the importance of the PP1 regulatory proteins for disease manifestation, provide an overview of genetic models to study the role of PP1 for the development of heart failure and atrial fibrillation and discuss possibilities of pharmacological interventions.
Topics: Calcium; Heart; Heart Failure; Humans; Phosphoprotein Phosphatases; Phosphorylation; Protein Phosphatase 1; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 34822978
DOI: 10.1016/j.cellsig.2021.110203 -
Brain Research Bulletin Nov 2023Postoperative cognitive dysfunction (POCD) is characterized by impaired learning and memory. 6 h duration isoflurane anesthesia is an important factor to induce POCD,...
BACKGROUND
Postoperative cognitive dysfunction (POCD) is characterized by impaired learning and memory. 6 h duration isoflurane anesthesia is an important factor to induce POCD, and the dysfunction of ryanodine receptor (RyR) in the hippocampus may be involved in this process. We investigated the expression of RyR3 in the hippocampus of mice after 6-h duration isoflurane anesthesia, as well as the improvement of RyR receptor agonist caffeine on POCD mice, while attempting to identify the underlying molecular mechanism.
MATERIALS
We constructed a POCD model using 8-week-old male C57BL/6J mice that were exposed to 6-h duration isoflurane. Prior to the three-day cognitive behavioral experiment, RyR agonist caffeine were injected. Fear conditioning and location memory tests were used in behavioral studies. We also exposed the mouse neuroblastoma cell line Neuro-2a (N2A) to 6-h duration isoflurane exposure to simulate the conditions of in vivo cognitive dysfunction. We administered ryanodine receptor agonist (caffeine) and inhibitor (ryanodine) to N2a cells. Following that, we performed a series of bioinformatics analysis to discover proteins that are involved in the development of cognitive dysfunction. Rt-PCR and Western blot were used to assess mRNA level and protein expression.
RESULTS
6-h duration isoflurane anesthesia induced cognitive dysfunction and increased RyR3 mRNA levels in hippocampus. The mRNA levels of RyR3 in cultured N2a cells after anesthesia were comparable to those in vivo, and the RyR agonist caffeine corrected the expression of some cognitive-related phenotypic proteins that were disturbed after anesthesia. Intraperitoneal injection of RyR agonist caffeine can improve cognitive function after isoflurane anesthesia in mice, and bioinformatics analyses suggest that CaMKⅣ may be involved in the molecular mechanism.
CONCLUSION
Ryanodine receptor agonist caffeine may improve cognitive dysfunction in mice after isoflurane anesthesia.
Topics: Male; Mice; Animals; Isoflurane; Ryanodine Receptor Calcium Release Channel; Anesthetics, Inhalation; Caffeine; Mice, Inbred C57BL; Cognitive Dysfunction; Postoperative Cognitive Complications; RNA, Messenger; Hippocampus
PubMed: 37852420
DOI: 10.1016/j.brainresbull.2023.110790 -
Cardiac Electrophysiology Clinics Sep 2023Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmia... (Review)
Review
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmia provoked by exercise or emotion. Most cases are caused by pathogenic variants in the gene encoding the cardiac ryanodine receptor (RYR2). The options for treating patients with CPVT have increased during the years, and evidence suggests that these have led to lower arrhythmic event rates. In addition, numerous potential new therapies are being investigated. In this review, we summarize the state of knowledge on both established and potential future treatment strategies for patients with CPVT and describe our approach to their management.
Topics: Humans; Anti-Arrhythmia Agents; Tachycardia, Ventricular; Exercise; Death, Sudden, Cardiac; Ryanodine Receptor Calcium Release Channel; Mutation
PubMed: 37558300
DOI: 10.1016/j.ccep.2023.04.002 -
The Journal of Physiology Jan 2023Enteroendocrine cells (EECs) are specialized sensors of luminal forces and chemicals in the gastrointestinal (GI) epithelium that respond to stimulation with a release...
Enteroendocrine cells (EECs) are specialized sensors of luminal forces and chemicals in the gastrointestinal (GI) epithelium that respond to stimulation with a release of signalling molecules such as serotonin (5-HT). For mechanosensitive EECs, force activates Piezo2 channels, which generate a very rapidly activating and inactivating (∼10 ms) cationic (Na , K , Ca ) receptor current. Piezo2 receptor currents lead to a large and persistent increase in intracellular calcium (Ca ) that lasts many seconds to sometimes minutes, suggesting signal amplification. However, intracellular calcium dynamics in EEC mechanotransduction remain poorly understood. The aim of this study was to determine the role of Ca stores in EEC mechanotransduction. Mechanical stimulation of a human EEC cell model (QGP-1) resulted in a rapid increase in cytoplasmic Ca and a slower decrease in ER stores Ca , suggesting the involvement of intracellular Ca stores. Comparing murine primary colonic EECs with colonocytes showed expression of intercellular Ca store receptors, a similar expression of IP receptors, but a >30-fold enriched expression of Ryr3 in EECs. In mechanically stimulated primary EECs, Ca responses decreased dramatically by emptying stores and pharmacologically blocking IP and RyR1/3 receptors. RyR3 genetic knockdown by siRNA led to a significant decrease in mechanosensitive Ca responses and 5-HT release. In tissue, pressure-induced increase in the Ussing short circuit current was significantly decreased by ryanodine receptor blockade. Our data show that mechanosensitive EECs use intracellular Ca stores to amplify mechanically induced Ca entry, with RyR3 receptors selectively expressed in EECs and involved in Ca signalling, 5-HT release and epithelial secretion. KEY POINTS: A population of enteroendocrine cells (EECs) are specialized mechanosensors of the gastrointestinal (GI) epithelium that respond to mechanical stimulation with the release of important signalling molecules such as serotonin. Mechanical activation of these EECs leads to an increase in intracellular calcium (Ca ) with a longer duration than the stimulus, suggesting intracellular Ca signal amplification. In this study, we profiled the expression of intracellular Ca store receptors and found an enriched expression of the intracellular Ca receptor Ryr3, which contributed to the mechanically evoked increases in intracellular calcium, 5-HT release and epithelial secretion. Our data suggest that mechanosensitive EECs rely on intracellular Ca stores and are selective in their use of Ryr3 for amplification of intracellular Ca . This work advances our understanding of EEC mechanotransduction and may provide novel diagnostic and therapeutic targets for GI motility disorders.
Topics: Mice; Animals; Humans; Ryanodine Receptor Calcium Release Channel; Ryanodine; Serotonin; Calcium; Receptors, Calcium-Sensing; Mechanotransduction, Cellular; Enteroendocrine Cells
PubMed: 36428286
DOI: 10.1113/JP283383 -
Journal of Agricultural and Food... Dec 2022Ryanodine receptor (RyR) is a giant calcium release channel located on the membrane of the endoplasmic reticulum (ER). Here, we report the regulation of RyRs from two...
Ryanodine receptor (RyR) is a giant calcium release channel located on the membrane of the endoplasmic reticulum (ER). Here, we report the regulation of RyRs from two major agricultural pests, diamondback moth and fall armyworm, by insect calmodulin (CaM). The recombinantly expressed full-length insect RyR could be pulled down by insect CaM in the presence of Ca, but the efficiency is lower compared to rabbit RyR1 and insect RyR with the CaM-binding domain (CaMBD) replaced by rabbit RyR1 sequence. Interestingly, the enhanced binding of CaM in the mutant insect RyR resulted in an increased sensitivity to the diamide insecticide chlorantraniliprole (CHL), suggesting that this CaM-CaMBD interface could be targeted by potential synergists acting as molecular glue. The thermodynamics of the binding between insect CaM and CaMBD was characterized by isothermal titration calorimetry, and the key residues responsible for the insect-specific regulation were identified through mutagenesis studies.
Topics: Animals; Rabbits; Calmodulin; Ryanodine Receptor Calcium Release Channel; Moths; Calcium Signaling; Protein Binding; Calcium
PubMed: 36524829
DOI: 10.1021/acs.jafc.2c07519 -
Advances in Anesthesia Dec 2019
Review
Topics: Calcium Channels, L-Type; Calcium-Binding Proteins; Calsequestrin; Comorbidity; Dantrolene; Genetic Predisposition to Disease; Humans; Incidence; Malignant Hyperthermia; Mitochondrial Proteins; Muscle Relaxants, Central; Perioperative Care; Prevalence; Ryanodine Receptor Calcium Release Channel
PubMed: 31677658
DOI: 10.1016/j.aan.2019.08.003 -
Cell Calcium Sep 2023The ryanodine receptor type 2 (RyR) is a key player in Ca handling during excitation-contraction coupling. During each heartbeat, RyR channels are responsible for...
The ryanodine receptor type 2 (RyR) is a key player in Ca handling during excitation-contraction coupling. During each heartbeat, RyR channels are responsible for linking the action potential with the contractile machinery of the cardiomyocyte by releasing Ca from the sarcoplasmic reticulum. RyR function is fine-tuned by associated signalling molecules, arrangement in clusters and subcellular localization. These parameters together define RyR function within microdomains and are subject to disease remodelling. This review describes the latest findings on RyR microdomain organization, the alterations with disease which result in increased subcellular heterogeneity and emergence of microdomains with enhanced arrhythmogenic potential, and presents novel technologies that guide future research to study and target RyR channels within specific microdomains.
PubMed: 37390591
DOI: 10.1016/j.ceca.2023.102769