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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 -
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 -
Philosophical Transactions of the Royal... Jun 2023Skeletal and cardiac muscle excitation-contraction coupling commences with Na1.4/Na1.5-mediated, surface and transverse (T-) tubular, action potential generation. This... (Review)
Review
Skeletal and cardiac muscle excitation-contraction coupling commences with Na1.4/Na1.5-mediated, surface and transverse (T-) tubular, action potential generation. This initiates , allosteric or Ca-mediated, T-sarcoplasmic reticular (SR) junctional, voltage sensor-Cav1.1/Cav1.2 and ryanodine receptor-RyR1/RyR2 interaction. We review recent structural, physiological and translational studies on possible actions of the resulting SR Ca release on Na1.4/Na1.5 function in native muscle. Finite-element modelling predicted potentially regulatory T-SR junctional [Ca] domains. Na1.4/Na1.5, III-IV linker and C-terminal domain structures included Ca and/or calmodulin-binding sites whose mutations corresponded to specific clinical conditions. Loose-patch-clamped native murine skeletal muscle fibres and cardiomyocytes showed reduced Na currents () following SR Ca release induced by the Epac and direct RyR1/RyR2 activators, 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphate and caffeine, abrogated by the RyR inhibitor dantrolene. Conversely, dantrolene and the Ca-ATPase inhibitor cyclopiazonic acid increased . Experimental, catecholaminergic polymorphic ventricular tachycardic and metabolically deficient cardiomyocytes also showed reduced accompanying [Ca] abnormalities rescued by dantrolene- and flecainide-mediated RyR block. Finally, hydroxychloroquine challenge implicated action potential (AP) prolongation in slowing AP conduction through modifying Ca transients. The corresponding tissue/organ preparations each showed pro-arrhythmic, slowed AP upstrokes and conduction velocities. We finally extend discussion of possible Ca-mediated effects to further, Ca, K and Cl, channel types. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Animals; Mice; Ryanodine Receptor Calcium Release Channel; Dantrolene; Feedback; Muscle, Skeletal; Action Potentials; Calcium
PubMed: 37122213
DOI: 10.1098/rstb.2022.0162 -
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 -
Annual Review of Physiology Feb 2022Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated... (Review)
Review
Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated calcium channels, calcium release via ryanodine receptors, and calcium reuptake and efflux via calcium-ATPase pumps and sodium-calcium exchangers. Agonists of the sympathetic nervous system bind to adrenergic receptors in cardiomyocytes, which, via cascading signal transduction pathways and protein kinase A (PKA), increase the heart rate (chronotropy), the strength of myocardial contraction (inotropy), and the rate of myocardial relaxation (lusitropy). These effects correlate with increased intracellular concentration of calcium, which is required for the augmentation of cardiomyocyte contraction. Despite extensive investigations, the molecular mechanisms underlying sympathetic nervous system regulation of calcium influx in cardiomyocytes have remained elusive over the last 40 years. Recent studies have uncovered the mechanisms underlying this fundamental biologic process, namely that PKA phosphorylates a calcium channel inhibitor, Rad, thereby releasing inhibition and increasing calcium influx. Here, we describe an updated model for how signals from adrenergic agonists are transduced to stimulate calcium influx and contractility in the heart.
Topics: Adrenergic Agents; Calcium; Calcium Channels, L-Type; Humans; Myocardial Contraction; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel
PubMed: 34752709
DOI: 10.1146/annurev-physiol-060121-041653 -
Nature Aug 2019The high-conductance intracellular calcium (Ca) channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle. Among various modulators,...
The high-conductance intracellular calcium (Ca) channel RyR2 is essential for the coupling of excitation and contraction in cardiac muscle. Among various modulators, calmodulin (CaM) regulates RyR2 in a Ca-dependent manner. Here we reveal the regulatory mechanism by which porcine RyR2 is modulated by human CaM through the structural determination of RyR2 under eight conditions. Apo-CaM and Ca-CaM bind to distinct but overlapping sites in an elongated cleft formed by the handle, helical and central domains. The shift in CaM-binding sites on RyR2 is controlled by Ca binding to CaM, rather than to RyR2. Ca-CaM induces rotations and intradomain shifts of individual central domains, resulting in pore closure of the PCB95 and Ca-activated channel. By contrast, the pore of the ATP, caffeine and Ca-activated channel remains open in the presence of Ca-CaM, which suggests that Ca-CaM is one of the many competing modulators of RyR2 gating.
Topics: Adenosine Triphosphate; Animals; Apoproteins; Binding Sites; Caffeine; Calcium; Calmodulin; Cryoelectron Microscopy; Humans; Models, Molecular; Reproducibility of Results; Ryanodine Receptor Calcium Release Channel; Swine
PubMed: 31278385
DOI: 10.1038/s41586-019-1377-y -
Clinical and Experimental Pharmacology... May 2023Dantrolene (DTN) is a ryanodine receptor (RyR) antagonist that inhibits Ca release from stores in the sarcoplasmic reticulum. DTN is mainly used in the management of... (Review)
Review
Dantrolene (DTN) is a ryanodine receptor (RyR) antagonist that inhibits Ca release from stores in the sarcoplasmic reticulum. DTN is mainly used in the management of malignant hyperthermia. RyRs are highly expressed in immune cells and are involved in different viral infections, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), because Ca is necessary for viral replication, maturation and release. DTN can inhibit the proliferation of SARS-CoV-2, indicating its potential role in reducing entry and pathogenesis of SARS-CoV-2. DTN may increase clearance of SARS-CoV-2 and promote coronavirus disease 2019 (COVID-19) recovery by shortening the period of infection. DTN inhibits N-methyl-D-aspartate (NMDA) mediated platelets aggregations and thrombosis. Therefore, DTN may inhibit thrombosis and coagulopathy in COVID-19 through suppression of platelet NMDA receptors. Moreover, DTN has a neuroprotective effect against SARS-CoV-2 infection-induced brain injury through modulation of NMDA receptors, which are involved in excitotoxicity, neuronal injury and the development of neuropsychiatric disorders. In conclusion, DTN by inhibiting RyRs may attenuate inflammatory disorders in SARS-CoV-2 infection and associated cardio-pulmonary complications. Therefore, DNT could be a promising drug therapy against COVID-19. Preclinical and clinical studies are warranted in this regards.
Topics: Humans; COVID-19; Dantrolene; Ryanodine Receptor Calcium Release Channel; SARS-CoV-2; Receptors, N-Methyl-D-Aspartate; Thrombosis
PubMed: 36732880
DOI: 10.1111/1440-1681.13756 -
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 -
Neural Regeneration Research Apr 2023Clinical disability following trauma or disease to the spinal cord often involves the loss of vital white matter elements including axons and glia. Although excessive Ca... (Review)
Review
Clinical disability following trauma or disease to the spinal cord often involves the loss of vital white matter elements including axons and glia. Although excessive Ca is an established driver of axonal degeneration, therapeutically targeting externally sourced Ca to date has had limited success in both basic and clinical studies. Contributing factors that may underlie this limited success include the complexity of the many potential sources of Ca entry and the discovery that axons also contain substantial amounts of stored Ca that if inappropriately released could contribute to axonal demise. Axonal Ca storage is largely accomplished by the axoplasmic reticulum that is part of a continuous network of the endoplasmic reticulum that provides a major sink and source of intracellular Ca from the tips of dendrites to axonal terminals. This "neuron-within-a-neuron" is positioned to rapidly respond to diverse external and internal stimuli by amplifying cytosolic Ca levels and generating short and long distance regenerative Ca waves through Ca induced Ca release. This review provides a glimpse into the molecular machinery that has been implicated in regulating ryanodine receptor mediated Ca release in axons and how dysregulation and/or overstimulation of these internodal axonal signaling nanocomplexes may directly contribute to Ca-dependent axonal demise. Neuronal ryanodine receptors expressed in dendrites, soma, and axonal terminals have been implicated in synaptic transmission and synaptic plasticity, but a physiological role for internodal localized ryanodine receptors remains largely obscure. Plausible physiological roles for internodal ryanodine receptors and such an elaborate internodal binary membrane signaling network in axons will also be discussed.
PubMed: 36204832
DOI: 10.4103/1673-5374.354512