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Physiological Reviews Jan 2022Ca-release channels are giant membrane proteins that control the release of Ca from the endoplasmic and sarcoplasmic reticulum. The two members, ryanodine receptors... (Review)
Review
Ca-release channels are giant membrane proteins that control the release of Ca from the endoplasmic and sarcoplasmic reticulum. The two members, ryanodine receptors (RyRs) and inositol-1,4,5-trisphosphate receptors (IPRs), are evolutionarily related and are both activated by cytosolic Ca. They share a common architecture, but RyRs have evolved additional modules in the cytosolic region. Their massive size allows for the regulation by tens of proteins and small molecules, which can affect the opening and closing of the channels. In addition to Ca, other major triggers include IP for the IPRs and depolarization of the plasma membrane for a particular RyR subtype expressed in skeletal muscle. Their size has made them popular targets for study via electron microscopic methods, with current structures culminating near 3 Å. The available structures have provided many new mechanistic insights into the binding of auxiliary proteins and small molecules, how these can regulate channel opening, and the mechanisms of disease-associated mutations. They also help scrutinize previously proposed binding sites, as some of these are now incompatible with the structures. Many questions remain around the structural effects of posttranslational modifications, additional binding partners, and the higher order complexes these channels can make in situ. This review summarizes our current knowledge about the structures of Ca-release channels and how this informs on their function.
Topics: Animals; Calcium; Calcium Signaling; Cell Membrane; Humans; Muscle, Skeletal; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 34280054
DOI: 10.1152/physrev.00033.2020 -
Neuromuscular Disorders : NMD Oct 2021Core myopathies are clinically, pathologically, and genetically heterogeneous muscle diseases. Their onset and clinical severity are variable. Core myopathies are... (Review)
Review
Core myopathies are clinically, pathologically, and genetically heterogeneous muscle diseases. Their onset and clinical severity are variable. Core myopathies are diagnosed by muscle biopsy showing focally reduced oxidative enzyme activity and can be pathologically divided into central core disease, multiminicore disease, dusty core disease, and core-rod myopathy. Although RYR1-related myopathy is the most common core myopathy, an increasing number of other causative genes have been reported, including SELENON, MYH2, MYH7, TTN, CCDC78, UNC45B, ACTN2, MEGF10, CFL2, KBTBD13, and TRIP4. Furthermore, the genes originally reported to cause nemaline myopathy, namely ACTA1, NEB, and TNNT1, have been recently associated with core-rod myopathy. Genetic analysis allows us to diagnose each core myopathy more accurately. In this review, we aim to provide up-to-date information about core myopathies.
Topics: Biopsy; Humans; Muscle Proteins; Muscle, Skeletal; Mutation; Myopathies, Nemaline; Myopathies, Structural, Congenital; Myopathy, Central Core; Ophthalmoplegia; Ryanodine Receptor Calcium Release Channel
PubMed: 34627702
DOI: 10.1016/j.nmd.2021.08.015 -
Acta Neuropathologica Jun 2020RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1...
RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1-RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1-RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1-RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.
Topics: Animals; Calcium; Cytoplasm; Humans; Muscle, Skeletal; Muscular Diseases; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 32236737
DOI: 10.1007/s00401-020-02150-w -
Channels (Austin, Tex.) Dec 2023Calcium ions (Ca) are the basis of a unique and potent array of cellular responses. Calmodulin (CaM) is a small but vital protein that is able to rapidly transmit... (Review)
Review
Calcium ions (Ca) are the basis of a unique and potent array of cellular responses. Calmodulin (CaM) is a small but vital protein that is able to rapidly transmit information about changes in Ca concentrations to its regulatory targets. CaM plays a critical role in cellular Ca signaling, and interacts with a myriad of target proteins. Ca-dependent modulation by CaM is a major component of a diverse array of processes, ranging from gene expression in neurons to the shaping of the cardiac action potential in heart cells. Furthermore, the protein sequence of CaM is highly evolutionarily conserved, and identical CaM proteins are encoded by three independent genes () in humans. Mutations within any of these three genes may lead to severe cardiac deficits including severe long QT syndrome (LQTS) and/or catecholaminergic polymorphic ventricular tachycardia (CPVT). Research into disease-associated CaM variants has identified several proteins modulated by CaM that are likely to underlie the pathogenesis of these calmodulinopathies, including the cardiac L-type Ca channel (LTCC) Ca1.2, and the sarcoplasmic reticulum Ca release channel, ryanodine receptor 2 (RyR2). Here, we review the research that has been done to identify calmodulinopathic CaM mutations and evaluate the mechanisms underlying their role in disease.
Topics: Humans; Calmodulin; Mutation; Tachycardia, Ventricular; Long QT Syndrome; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel; Calcium
PubMed: 36629534
DOI: 10.1080/19336950.2023.2165278 -
Cardiology in Review 2020Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare congenital arrhythmogenic disorder induced by physical or emotional stress. It mainly affects... (Review)
Review
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare congenital arrhythmogenic disorder induced by physical or emotional stress. It mainly affects children and younger adults and is characterized by rapid polymorphic and bidirectional ventricular tachycardia. Symptoms can include dizziness, palpitations, and presyncope, which may progress to syncope, hypotonia, convulsive movements, and sudden cardiac death. CPVT is the result of perturbations in Ca ion handling in the sarcoplasmic reticulum of cardiac myocytes. Mutations in the cardiac ryanodine receptor gene and the calsequestrin isoform 2 gene are most commonly seen in familial CPVT patients. Under catecholaminergic stimulation, either mutation can result in an excess Ca load during diastole resulting in delayed after depolarization and subsequent arrhythmogenesis. The current first-line treatment for CPVT is β-blocker therapy. Other therapeutic interventions that can be used in conjunction with β-blockers include moderate exercise training, flecainide, left cardiac sympathetic denervation, and implantable cardioverter-defibrillators. Several potential therapeutic interventions, including verapamil, dantrolene, JTV519, and gene therapy, are also discussed.
Topics: Calsequestrin; Disease Management; Humans; Mutation; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular
PubMed: 31934898
DOI: 10.1097/CRD.0000000000000302 -
Current Pharmaceutical Design 2022The ryanodine receptor (RyR) is one of the primary targets of commercial insecticides. The diamide insecticide family, including flubendiamide, chlorantraniliprole,... (Review)
Review
The ryanodine receptor (RyR) is one of the primary targets of commercial insecticides. The diamide insecticide family, including flubendiamide, chlorantraniliprole, cyantraniliprole, etc., targets insect RyRs and can be used to control a wide range of destructive agricultural pests. The diamide insecticides are highly selective against lepidopteran and coleopteran pests with relatively low toxicity for non-target species, such as mammals, fishes, and beneficial insects. However, recently mutations identified on insect RyRs have emerged and caused resistance in several major agricultural pests throughout different continents. This review paper summarizes the recent findings on the structure and function of insect RyRs as insecticide targets. Specifically, we examine the structures of RyRs from target and non-target species, which reveals the molecular basis for insecticide action and selectivity. We also examine the structural and functional changes of RyR caused by the resistance mutations. Finally, we examine the progress in RyR structure-based insecticide design and discuss how this might help the development of a new generation of green insecticides.
Topics: Animals; Calcium Signaling; Diamide; Humans; Insecticide Resistance; Insecticides; Mammals; Ryanodine Receptor Calcium Release Channel
PubMed: 34477510
DOI: 10.2174/1381612827666210902150224 -
Circulation Research Jul 2023
Topics: Ryanodine Receptor Calcium Release Channel; Myocytes, Cardiac; Calcium Signaling; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Sarcoplasmic Reticulum
PubMed: 37410856
DOI: 10.1161/CIRCRESAHA.123.323144 -
Heart, Lung & Circulation Jul 2023Over the last three decades, the genetic basis of various inherited arrhythmia syndromes has been elucidated, providing key insights into cardiomyocyte biology and... (Review)
Review
Over the last three decades, the genetic basis of various inherited arrhythmia syndromes has been elucidated, providing key insights into cardiomyocyte biology and various regulatory pathways associated with cellular excitation, contraction, and repolarisation. As varying techniques to manipulate genetic sequence, gene expression, and different cellular pathways have become increasingly defined and understood, the potential to apply various gene-based therapies to inherited arrhythmia has been explored. The promise of gene therapy has generated significant interest in the medical and lay press, providing hope for sufferers of seemingly incurable disorders to imagine a future without repeated medical intervention, and, in the case of various cardiac disorders, without the risk of sudden death. In this review, we focus on catecholaminergic polymorphic ventricular tachycardia (CPVT), discussing the clinical manifestations, genetic basis, and molecular biology, together with current avenues of research related to gene therapy.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular; Genetic Therapy; Myocytes, Cardiac; Mutation
PubMed: 37032191
DOI: 10.1016/j.hlc.2023.01.018 -
Journal of the American Chemical Society Jul 2020A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway...
A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.
Topics: Biological Products; Cyclization; Molecular Structure; Ryanodine; Stereoisomerism
PubMed: 32609506
DOI: 10.1021/jacs.0c05766