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ESC Heart Failure Aug 2021Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy. Excessive hyperglycaemia increases the levels of reactive carbonyl species... (Review)
Review
Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy. Excessive hyperglycaemia increases the levels of reactive carbonyl species (RCS), reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the heart and causes derangements in calcium homeostasis, inflammation and immune-system disorders. Ryanodine receptor 2 (RyR2) plays a key role in excitation-contraction coupling during heart contractions, including rhythmic contraction and relaxation of the heart. Cardiac inflammation has been indicated in part though interleukin 1 (IL-1) signals, supporting a role for B and T lymphocytes in diabetic cardiomyopathy. Some of the post-translational modifications of the ryanodine receptor (RyR) by RCS, ROS and RNS stress are known to affect its gating and Ca sensitivity, which contributes to RyR dysregulation in diabetic cardiomyopathy. RyRs and immune-related molecules are important signalling species in many physiological and pathophysiological processes in various heart and cardiovascular diseases. However, little is known regarding the mechanistic relationship between RyRs and immune-related molecules in diabetes, as well as the mechanisms mediating complex communication among cardiomyocytes, fibroblasts and immune cells. This review highlights new findings on the complex cellular communications in the pathogenesis and progression of diabetic cardiomyopathy. We discuss potential therapeutic applications targeting RyRs and immune-related molecules in diabetic complications.
Topics: Calcium Signaling; Diabetes Mellitus; Diabetic Cardiomyopathies; Homeostasis; Humans; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel
PubMed: 34013670
DOI: 10.1002/ehf2.13431 -
International Journal of Molecular... Apr 2022Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most... (Review)
Review
Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most relevant aim of cardiac research is to unravel the molecular pathomechanisms and identify new therapeutic targets. Cardiac ryanodine receptor (RyR2), the Ca release channel of the sarcoplasmic reticulum, is believed to be a good therapeutic target in a group of certain heart diseases, collectively called cardiac ryanopathies. Ryanopathies are associated with the impaired function of the RyR, leading to heart diseases such as congestive heart failure (CHF), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and calcium release deficiency syndrome (CRDS). The aim of the current review is to provide a short insight into the pathological mechanisms of ryanopathies and discuss the pharmacological approaches targeting RyR2.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Calcium; Calcium Signaling; Humans; Mutation; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Tachycardia, Ventricular
PubMed: 35457253
DOI: 10.3390/ijms23084435 -
Biochimica Et Biophysica Acta.... Nov 2018Regulation of intracellular calcium (Ca) is critical in all cell types. The ryanodine receptor (RyR), an intracellular Ca release channel located on the... (Review)
Review
Regulation of intracellular calcium (Ca) is critical in all cell types. The ryanodine receptor (RyR), an intracellular Ca release channel located on the sarco/endoplasmic reticulum (SR/ER), releases Ca from intracellular stores to activate critical functions including muscle contraction and neurotransmitter release. Dysfunctional RyR-mediated Ca handling has been implicated in the pathogenesis of inherited and non-inherited conditions including heart failure, cardiac arrhythmias, skeletal myopathies, diabetes, and neurodegenerative diseases. Here we have reviewed the evidence linking human disorders to RyR dysfunction and describe novel approaches to RyR-targeted therapeutics.
Topics: Animals; Calcium; Calcium Signaling; Calmodulin; Carrier Proteins; Disease Susceptibility; Endoplasmic Reticulum; Humans; Ion Channel Gating; Ligands; Phosphorylation; Protein Binding; Ryanodine Receptor Calcium Release Channel
PubMed: 30040966
DOI: 10.1016/j.bbamcr.2018.07.011 -
Sub-cellular Biochemistry 2018Ryanodine receptors (RyRs) are ubiquitous intracellular calcium (Ca) release channels required for the function of many organs including heart and skeletal muscle,... (Review)
Review
Ryanodine receptors (RyRs) are ubiquitous intracellular calcium (Ca) release channels required for the function of many organs including heart and skeletal muscle, synaptic transmission in the brain, pancreatic beta cell function, and vascular tone. In disease, defective function of RyRs due either to stress (hyperadrenergic and/or oxidative overload) or genetic mutations can render the channels leaky to Ca and promote defective disease-causing signals as observed in heat failure, muscular dystrophy, diabetes mellitus, and neurodegerative disease. RyRs are massive structures comprising the largest known ion channel-bearing macromolecular complex and exceeding 3 million Daltons in molecular weight. RyRs mediate the rapid release of Ca from the endoplasmic/sarcoplasmic reticulum (ER/SR) to stimulate cellular functions through Ca-dependent processes. Recent advances in single-particle cryogenic electron microscopy (cryo-EM) have enabled the determination of atomic-level structures for RyR for the first time. These structures have illuminated the mechanisms by which these critical ion channels function and interact with regulatory ligands. In the present chapter we discuss the structure, functional elements, gating and activation mechanisms of RyRs in normal and disease states.
Topics: Animals; Calcium; Calcium Signaling; Diabetes Mellitus; Humans; Muscular Dystrophies; Mutation; Neurodegenerative Diseases; Ryanodine Receptor Calcium Release Channel; Synaptic Transmission
PubMed: 29464565
DOI: 10.1007/978-981-10-7757-9_11 -
Aging Dec 2020
Topics: Aging; Animals; Calcium; Calcium Channels, L-Type; Calcium Channels, T-Type; Calcium Signaling; Hemodynamics; Homeostasis; Hypertension; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Ryanodine Receptor Calcium Release Channel; Vasoconstriction
PubMed: 33361526
DOI: 10.18632/aging.104220 -
Circulation Research Sep 2018
Topics: CRISPR-Cas Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Humans; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular
PubMed: 30355043
DOI: 10.1161/CIRCRESAHA.118.313876 -
Biochemical and Biophysical Research... Aug 2023As a Lepidoptera pest, Spodoptera frugiperda has become one of the major migratory pests causing significant damage to crops. It should prevent and control Spodoptera... (Review)
Review
As a Lepidoptera pest, Spodoptera frugiperda has become one of the major migratory pests causing significant damage to crops. It should prevent and control Spodoptera frugiperda with strong reproductive ability, adaptability, and migration ability, and reduce economic losses as much as possible. Chemical insecticides are mainly used in the emergency control of Spodoptera frugiperda. Diamide insecticide is a kind of pesticide that specifically targets the ryanodine receptor of Lepidopteran pests, which makes it safe, effective, targeted, and low toxicity to mammals. So, it is one of the most concerned and fastest-growing pesticide products after neonicotinoid pesticides. Intracellular Ca concentration can be regulated by ryanodine receptors, and the continuous release of Ca eventually leads to the death of pests and achieve the insecticidal effect. This review introduces in detail diamide insecticides that mainly play roles in stomach toxicity, as well as its specific target-ryanodine receptor, and analyzes how the diamide insecticide acts on the ryanodine receptor and how its mechanism of action can provide a theoretical basis for the rational use of highly effective insecticides and solve the resistance problem. Moreover, we also propose several recommendations for reducing resistance to diamide insecticides, and provide a reference for chemical control and resistance studies of Spodoptera frugiperda, which has broad development prospects in today's increasingly concerned about the ecological environment and advocating green environmental protection.
Topics: Animals; Insecticides; Ryanodine Receptor Calcium Release Channel; Diamide; Insecticide Resistance; Spodoptera; Mammals
PubMed: 37271036
DOI: 10.1016/j.bbrc.2023.05.107 -
Trends in Biochemical Sciences Jul 2017Ryanodine receptors (RyRs) are calcium release channels expressed in the sarcoendoplasmic reticula of many cell types including cardiac and skeletal muscle cells. In... (Review)
Review
Ryanodine receptors (RyRs) are calcium release channels expressed in the sarcoendoplasmic reticula of many cell types including cardiac and skeletal muscle cells. In recent years Ca leak through RyRs has been implicated as a major contributor to the development of diseases including heart failure, muscle myopathies, Alzheimer's disease, and diabetes, making it an important therapeutic target. Recent mammalian RyR1 cryoelectron microscopy (cryo-EM) structures of multiple functional states have clarified longstanding questions including the architecture of the transmembrane (TM) pore and cytoplasmic domains, the location and architecture of the channel gate, ligand-binding sites, and the gating mechanism. As we advance toward complete models of RyRs this new information enables the determination of domain-domain interfaces and the location and structural effects of disease-causing RyR mutations.
Topics: Animals; Calcium; Humans; Models, Molecular; Ryanodine Receptor Calcium Release Channel
PubMed: 28499500
DOI: 10.1016/j.tibs.2017.04.005 -
Current Opinion in Pharmacology Apr 2023Type 1 ryanodine receptor (RyR1) is an intracellular Ca release channel on the sarcoplasmic reticulum of skeletal muscle, and it plays a central role in... (Review)
Review
Type 1 ryanodine receptor (RyR1) is an intracellular Ca release channel on the sarcoplasmic reticulum of skeletal muscle, and it plays a central role in excitation-contraction (E-C) coupling. Mutations in RyR1 are implicated in various muscle diseases including malignant hyperthermia, central core disease, and myopathies. Currently, no specific treatment exists for most of these diseases. Recently, high-throughput screening (HTS) assays have been developed for identifying potential candidates for treating RyR-related muscle diseases. Currently, two different methods, namely a FRET-based assay and an endoplasmic reticulum Ca-based assay, are available. These assays identified several compounds as novel RyR1 inhibitors. In addition, the development of a reconstituted platform permitted HTS assays for E-C coupling modulators. In this review, we will focus on recent progress in HTS assays and discuss future perspectives of these promising approaches.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Muscular Diseases; Calcium Signaling; Muscle, Skeletal; Drug Development; Calcium; Mutation
PubMed: 36842386
DOI: 10.1016/j.coph.2023.102356 -
Revista Espanola de Anestesiologia Y... Jan 2017Malignant hyperthermia is a hypermetabolic syndrome that appears in susceptible patients after exposure to certain anaesthetic drugs (succinylcholine, inhalation... (Review)
Review
Malignant hyperthermia is a hypermetabolic syndrome that appears in susceptible patients after exposure to certain anaesthetic drugs (succinylcholine, inhalation anaesthetics). Its incidence in Spain is 1 in 40,000 adults, with a 10% mortality rate. It is induced by an abnormal regulation of the ryanodine receptors, producing a massive release of calcium from the sarcoplasmic reticulum in the striate muscle. Clinical manifestations include: CO increase, tachycardia, haemodynamic instability, metabolic and respiratory acidosis, profuse sweating, hyperpyrexia, CPK increase, myoglobinuria, kidney failure, disseminated intravascular coagulation (DIC), and ending in cardiac arrest. Dantrolene sodium is a ryanodine receptor antagonist, and inhibits the release of intracellular calcium. Definitive diagnosis is achieved by the exposure of muscle fibres to caffeine and halothane. Protocols can help guarantee a reliable and secure management when this severe event occurs.
Topics: Adolescent; Adult; Caffeine; Calcium Signaling; Child; Child, Preschool; Clinical Protocols; Critical Care; Dantrolene; Diagnosis, Differential; Disease Management; Female; Halothane; Humans; Infant; Infant, Newborn; Male; Malignant Hyperthermia; Muscle Contraction; Muscle Fibers, Skeletal; Neuroleptic Malignant Syndrome; Ryanodine Receptor Calcium Release Channel; Serotonin Syndrome
PubMed: 27633384
DOI: 10.1016/j.redar.2016.06.004