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The Journal of Physiology Oct 2021Ryanodine receptors (RyRs) are intracellular Ca release channels ubiquitously expressed in various cell types. RyRs were extensively studied in striated muscle cells due...
Ryanodine receptors (RyRs) are intracellular Ca release channels ubiquitously expressed in various cell types. RyRs were extensively studied in striated muscle cells due to their crucial role in muscle contraction. In contrast, the role of RyRs in Ca signalling and functions in non-excitable cells, such as T lymphocytes, remains poorly understood. Expression of different isoforms of RyRs was shown in primary T cells and T cell lines. In T cells, RyRs co-localize with the plasmalemmal store-operated Ca channels of the Orai family and endoplasmic reticulum Ca sensing Stim family proteins and are activated by store-operated Ca entry and pyridine nucleotide metabolites, the intracellular second messengers generated upon stimulation of T cell receptors. Experimental data indicate that together with d-myo-inositol 1,4,5-trisphosphate receptors, RyRs regulate intercellular Ca dynamics by controlling Ca concentration within the lumen of the endoplasmic reticulum and, consequently, store-operated Ca entry. Gain-of-function mutations, genetic deletion or pharmacological inhibition of RyRs alters T cell Ca signalling and effector functions. The picture emerging from the collective data shows that RyRs are the essential regulators of T cell Ca signalling and can be potentially used as molecular targets for immunomodulation or T cell-based diagnostics of the disorders associated with RyRs dysregulation.
Topics: Calcium; Calcium Signaling; Inositol 1,4,5-Trisphosphate Receptors; Receptors, Antigen, T-Cell; Ryanodine; Ryanodine Receptor Calcium Release Channel; T-Lymphocytes
PubMed: 34411300
DOI: 10.1113/JP281722 -
Cell Calcium Dec 2020Defective ER/SR-cytosol Ca cycling is associated with increased ER stress, pathological heart conditions and muscular defects. Within the SR, ryanodine receptor 2 (RyR2)...
Defective ER/SR-cytosol Ca cycling is associated with increased ER stress, pathological heart conditions and muscular defects. Within the SR, ryanodine receptor 2 (RyR2) is required for excitation/contraction coupling. Ca release from the SR is counterbalanced by K influx through trimeric intracellular cation (TRIC) channels to maintain ER/SR polarity. New functions of TRIC channels have been discovered.
Topics: Calcium; Calcium Signaling; Cations; Excitation Contraction Coupling; Ryanodine Receptor Calcium Release Channel; Stromal Interaction Molecule 1
PubMed: 32979765
DOI: 10.1016/j.ceca.2020.102290 -
The Journal of Clinical Investigation Dec 2023The suppression mechanism of Tregs remains an intensely investigated topic. As our focus has shifted toward a model centered on indirect inhibition of DCs, a universally...
The suppression mechanism of Tregs remains an intensely investigated topic. As our focus has shifted toward a model centered on indirect inhibition of DCs, a universally applicable effector mechanism controlled by the transcription factor forkhead box P3 (Foxp3) expression has not been found. Here, we report that Foxp3 blocked the transcription of ER Ca2+-release channel ryanodine receptor 2 (RyR2). Reduced RyR2 shut down basal Ca2+ oscillation in Tregs, which reduced m-calpain activities that are needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency rendered the CD4+ T cell pool immune suppressive and caused it to behave in the same manner as Foxp3+ Tregs in viral infection, asthma, hypersensitivity, colitis, and tumor development. In the absence of Foxp3, Ryr2-deficient CD4+ T cells rescued the systemic autoimmunity associated with scurfy mice. Therefore, Foxp3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression.
Topics: Animals; Mice; Calcium; CD4-Positive T-Lymphocytes; Forkhead Transcription Factors; Gene Expression Regulation; Ryanodine Receptor Calcium Release Channel; T-Lymphocytes, Regulatory
PubMed: 38099494
DOI: 10.1172/JCI163470 -
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