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Advances in Experimental Medicine and... 2021Ca/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional protein kinase and has been recently recognized to play a vital role in pathological events in... (Review)
Review
Ca/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional protein kinase and has been recently recognized to play a vital role in pathological events in the pulmonary system. CaMKII has diverse downstream targets that promote vascular disease, asthma, and cancer, so improved understanding of CaMKII signaling has the potential to lead to new therapies for lung diseases. Multiple studies have demonstrated that CaMKII is involved in redox modulation of ryanodine receptors (RyRs). CaMKII can be directly activated by reactive oxygen species (ROS) which then regulates RyR activity, which is essential for Ca-dependent processes in lung diseases. Furthermore, both CaMKII and RyRs participate in the inflammation process. However, their role in the pulmonary physiology in response to ROS is still an ambiguous one. Because CaMKII and RyRs are important in pulmonary biology, cell survival, cell cycle control, and inflammation, it is possible that the relationship between ROS and CaMKII/RyRs signal complex will be necessary for understanding and treating lung diseases. Here, we review roles of CaMKII/RyRs in lung diseases to understand with how CaMKII/RyRs may act as a transduction signal to connect prooxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of pulmonary disease.
Topics: Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Humans; Inflammation; Lung Diseases; Ryanodine; Ryanodine Receptor Calcium Release Channel
PubMed: 33788199
DOI: 10.1007/978-3-030-63046-1_16 -
Cardiovascular Diabetology Oct 2023O-GlcNAcylation is the enzymatic addition of a sugar, O-linked β-N-Acetylglucosamine, to the serine and threonine residues of proteins, and is abundant in diabetic...
BACKGROUND
O-GlcNAcylation is the enzymatic addition of a sugar, O-linked β-N-Acetylglucosamine, to the serine and threonine residues of proteins, and is abundant in diabetic conditions. We have previously shown that O-GlcNAcylation can trigger arrhythmias by indirectly increasing pathological Ca leak through the cardiac ryanodine receptor (RyR2) via Ca/calmodulin-dependent kinase II (CaMKII). However, RyR2 is well known to be directly regulated by other forms of serine and threonine modification, therefore, this study aimed to determine whether RyR2 is directly modified by O-GlcNAcylation and if this also alters the function of RyR2 and Ca leak.
METHODS
O-GlcNAcylation of RyR2 in diabetic human and animal hearts was determined using western blotting. O-GlcNAcylation of RyR2 was pharmacologically controlled and the propensity for Ca leak was determined using single cell imaging. The site of O-GlcNAcylation within RyR2 was determined using site-directed mutagenesis of RyR2.
RESULTS
We found that RyR2 is modified by O-GlcNAcylation in human, animal and HEK293 cell models. Under hyperglycaemic conditions O-GlcNAcylation was associated with an increase in Ca leak through RyR2 which persisted after CaMKII inhibition. Conversion of serine-2808 to alanine prevented an O-GlcNAcylation induced increase in Ca leak.
CONCLUSIONS
These data suggest that the function of RyR2 can be directly regulated by O-GlcNAcylation and requires the presence of serine-2808.
Topics: Animals; Humans; Ryanodine Receptor Calcium Release Channel; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Myocytes, Cardiac; HEK293 Cells; Phosphorylation; Sarcoplasmic Reticulum; Diabetes Mellitus; Serine; Threonine; Calcium
PubMed: 37833717
DOI: 10.1186/s12933-023-02010-3 -
Cell Calcium Dec 2023Ryanodine receptors (RyR) are intracellular Ca channels localized in the endoplasmic reticulum, where they act as critical mediators of Ca-induced Ca calcium release... (Review)
Review
Ryanodine receptors (RyR) are intracellular Ca channels localized in the endoplasmic reticulum, where they act as critical mediators of Ca-induced Ca calcium release (CICR). In the brain, mammals express in both neurons, and non-neuronal cells, a combination of the three RyR-isoforms (RyR1-3). Pharmacological approaches, which do not distinguish between isoforms, have indicated that RyR-isoforms contribute to brain function. However, isoform-specific manipulations have revealed that RyR-isoforms display different subcellular localizations and are differentially associated with neuronal function. These findings raise the need to understand RyR-isoform specific transcriptional regulation, as this knowledge will help to elucidate the causes of neuronal dysfunction for a growing list of brain disorders that show altered RyR channel expression and function.
Topics: Animals; Ryanodine Receptor Calcium Release Channel; Endoplasmic Reticulum; Gene Expression Regulation; Brain; Calcium; Protein Isoforms; Ryanodine; Mammals
PubMed: 37949035
DOI: 10.1016/j.ceca.2023.102821 -
Alzheimer's & Dementia : the Journal of... May 2022The mechanisms that lead to cognitive impairment associated with COVID-19 are not well understood.
INTRODUCTION
The mechanisms that lead to cognitive impairment associated with COVID-19 are not well understood.
METHODS
Brain lysates from control and COVID-19 patients were analyzed for oxidative stress and inflammatory signaling pathway markers, and measurements of Alzheimer's disease (AD)-linked signaling biochemistry. Post-translational modifications of the ryanodine receptor/calcium (Ca2 ) release channels (RyR) on the endoplasmic reticuli (ER), known to be linked to AD, were also measured by co-immunoprecipitation/immunoblotting of the brain lysates.
RESULTS
We provide evidence linking SARS-CoV-2 infection to activation of TGF-β signaling and oxidative overload. The neuropathological pathways causing tau hyperphosphorylation typically associated with AD were also shown to be activated in COVID-19 patients. RyR2 in COVID-19 brains demonstrated a "leaky" phenotype, which can promote cognitive and behavioral defects.
DISCUSSION
COVID-19 neuropathology includes AD-like features and leaky RyR2 channels could be a therapeutic target for amelioration of some cognitive defects associated with SARS-CoV-2 infection and long COVID.
Topics: Alzheimer Disease; Brain; COVID-19; Calcium Signaling; Humans; Ryanodine Receptor Calcium Release Channel; SARS-CoV-2; Post-Acute COVID-19 Syndrome
PubMed: 35112786
DOI: 10.1002/alz.12558 -
Advances in Experimental Medicine and... 2020Calcium signaling regulates secretion of hormones and many other cellular processes in the islets of Langerhans. The three subtypes of the inositol 1,4,5-trisphosphate... (Review)
Review
Expression of the Inositol 1,4,5-Trisphosphate Receptor and the Ryanodine Receptor Ca-Release Channels in the Beta-Cells and Alpha-Cells of the Human Islets of Langerhans.
Calcium signaling regulates secretion of hormones and many other cellular processes in the islets of Langerhans. The three subtypes of the inositol 1,4,5-trisphosphate receptors (IP3Rs), inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), 1,4,5-trisphosphate receptor type 2 (IP3R2), 1,4,5-trisphosphate receptor type 3 (IP3R3), and the three subtypes of the ryanodine receptors (RyRs), ryanodine receptor 1 (RyR1), ryanodine receptor 2 (RyR2) and ryanodine receptor 3 (RyR3) are the main intracellular Ca-release channels. The identity and the relative levels of expression of these channels in the alpha-cells, and the beta-cells of the human islets of Langerhans are unknown. We have analyzed the RNA sequencing data obtained from highly purified human alpha-cells and beta-cells for quantitatively identifying the mRNA of the intracellular Ca-release channels in these cells. We found that among the three IP3Rs the IP3R3 is the most abundantly expressed one in the beta-cells, whereas IP3R1 is the most abundantly expressed one in the alpha-cells. In addition to the IP3R3, beta-cells also expressed the IP3R2, at a lower level. Among the RyRs, the RyR2 was the most abundantly expressed one in the beta-cells, whereas the RyR1 was the most abundantly expressed one in the alpha-cells. Information on the relative abundance of the different intracellular Ca-release channels in the human alpha-cells and the beta-cells may help the understanding of their roles in the generation of Ca signals and many other related cellular processes in these cells.
Topics: Calcium Signaling; Gene Expression Regulation; Humans; Inositol 1,4,5-Trisphosphate Receptors; Ryanodine Receptor Calcium Release Channel
PubMed: 31646514
DOI: 10.1007/978-3-030-12457-1_11 -
International Journal of Molecular... Oct 2021The ryanodine receptor (RyR) is a Ca release channel in the sarcoplasmic reticulum of skeletal and cardiac muscles and plays a key role in excitation-contraction... (Review)
Review
The ryanodine receptor (RyR) is a Ca release channel in the sarcoplasmic reticulum of skeletal and cardiac muscles and plays a key role in excitation-contraction coupling. The activity of the RyR is regulated by the changes in the level of many intracellular factors, such as divalent cations (Ca and Mg), nucleotides, associated proteins, and reactive oxygen species. Since these intracellular factors change depending on the condition of the muscle, e.g., exercise, fatigue, or disease states, the RyR channel activity will be altered accordingly. In this review, we describe how the RyR channel is regulated under various conditions and discuss the possibility that the RyR acts as a sensor for changes in the intracellular environments in muscles.
Topics: Animals; Calcium; Humans; Muscle Contraction; Muscle, Skeletal; Myocardium; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 34639137
DOI: 10.3390/ijms221910795 -
Circulation Research Jun 2021
Topics: Arrhythmias, Cardiac; Humans; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 34166076
DOI: 10.1161/CIRCRESAHA.121.319449 -
Critical Care Medicine Dec 2020Mechanical ventilation is associated with primary diaphragmatic dysfunction, also termed ventilator-induced diaphragmatic dysfunction. Studies evaluating diaphragmatic...
OBJECTIVES
Mechanical ventilation is associated with primary diaphragmatic dysfunction, also termed ventilator-induced diaphragmatic dysfunction. Studies evaluating diaphragmatic function recovery after extubation are lacking. We evaluated early and late recoveries from ventilator-induced diaphragmatic dysfunction in a mouse model.
DESIGN
Experimental randomized study.
SETTING
Research laboratory.
SUBJECTS
C57/BL6 mice.
INTERVENTIONS
Six groups of C57/BL6 mice. Mice were ventilated for 6 hours and then euthanatized immediately (n = 18), or 1 (n = 18) or 10 days after extubation with (n = 5) and without S107 (n = 16) treatment. Mice euthanatized immediately after 6 hours of anesthesia (n = 15) or after 6 hours of anesthesia and 10 days of recovery (n = 5) served as controls.
MEASUREMENTS AND MAIN RESULTS
For each group, diaphragm force production, posttranslational modification of ryanodine receptor, oxidative stress, proteolysis, and cross-sectional areas were evaluated. After 6 hours of mechanical ventilation, diaphragm force production was decreased by 25-30%, restored to the control levels 1 day after extubation, and secondarily decreased by 20% 10 days after extubation compared with controls. Ryanodine receptor was protein kinase A-hyperphosphorylated, S-nitrosylated, oxidized, and depleted of its stabilizing subunit calstabin-1 6 hours after the onset of the mechanical ventilation, 1 and 10 days after extubation. Post extubation treatment with S107, a Rycal drug that stabilizes the ryanodine complex, did reverse the loss of diaphragmatic force associated with mechanical ventilation. Total protein oxidation was restored to the control levels 1 day after extubation. Markers of proteolysis including calpain 1 and calpain 2 remained activated 10 days after extubation without significant changes in cross-sectional areas.
CONCLUSIONS
We report that mechanical ventilation is associated with a late diaphragmatic dysfunction related to a structural alteration of the ryanodine complex that is reversed with the S107 treatment.
Topics: Airway Extubation; Animals; Blotting, Western; Diaphragm; Disease Models, Animal; Immunoprecipitation; Mice; Mice, Inbred C57BL; Oxidative Stress; Proteolysis; Respiration, Artificial; Ryanodine Receptor Calcium Release Channel
PubMed: 33009102
DOI: 10.1097/CCM.0000000000004569 -
Circulation Research Feb 2024
Topics: Calcium-Binding Proteins; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Calcium
PubMed: 38300986
DOI: 10.1161/CIRCRESAHA.124.324109 -
Current management of inherited arrhythmia syndromes associated with the cardiac ryanodine receptor.Current Opinion in Cardiology Jul 2023Gain-of-function variants in the gene encoding the cardiac ryanodine receptor ( RYR2 ) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT).... (Review)
Review
PURPOSE OF REVIEW
Gain-of-function variants in the gene encoding the cardiac ryanodine receptor ( RYR2 ) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). The exercise stress test (EST) has long been fundamental in diagnosis and management, but recent work has further explored its role. A new entity termed calcium release deficiency syndrome (CRDS) has been associated with loss-of-function RYR2 variants and a different arrhythmic phenotype.
RECENT FINDINGS
Standard EST is not perfectly reproducible with regards to provocation of arrhythmia in CPVT. A newly described burst EST protocol may be more sensitive in this regard. Nadolol is the most effective beta blocker in CPVT, though arrhythmic events remain frequent and dual therapy with flecainide and/or left cardiac sympathetic denervation may add protection. A recent report renews debate regarding the use of implantable defibrillator therapy in CPVT. CRDS is characterized by later age of presentation, normal/near normal EST, and ventricular arrhythmia induced by a novel ventricular stimulation protocol.
SUMMARY
Burst EST may aid in the diagnosis and management of CPVT. Nadolol is the preferred beta blocker in CPVT, and consideration should be given to early dual therapy. CRDS should be suspected in patients with arrhythmic events, rare RYR2 variants, and a phenotype inconsistent with CPVT.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Nadolol; Flecainide; Tachycardia, Ventricular; Adrenergic beta-Antagonists; Mutation
PubMed: 37016946
DOI: 10.1097/HCO.0000000000001051