-
Science Signaling Jun 2020In this issue of , Thakore report that the Ca-permeable channel TRPML1 closely associates with ryanodine receptors to induce Ca sparks in native arterial myocytes.... (Review)
Review
In this issue of , Thakore report that the Ca-permeable channel TRPML1 closely associates with ryanodine receptors to induce Ca sparks in native arterial myocytes. Functional studies revealed a key role for TRPML1 channels in regulation of arterial myocyte contractility and blood pressure.
Topics: Calcium; Calcium Signaling; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Ryanodine Receptor Calcium Release Channel
PubMed: 32576679
DOI: 10.1126/scisignal.abc0993 -
Current Pharmaceutical Design 2022
Topics: Acetylcholine; Calcium; Humans; Ryanodine Receptor Calcium Release Channel
PubMed: 35043758
DOI: 10.2174/138161282801211223123314 -
Current Opinion in Pharmacology Feb 2023Myopathies related to variations in the RYR1 gene are genetic diseases for which the therapeutic options are sparse, in part because of the very large size of the gene... (Review)
Review
Myopathies related to variations in the RYR1 gene are genetic diseases for which the therapeutic options are sparse, in part because of the very large size of the gene and protein, and of the distribution of variations all along the sequence. Taking advantage of the progress made in the gene therapy field, different approaches can be applied to the different genetic variations, either at the mRNA level or directly at the DNA level, specifically with the new gene editing tools. Some of those have already been tested in cellulo and/or in vivo, and for the development of the most innovative gene editing technology, inspiration can be sought in other genetic diseases.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Muscular Diseases; Muscle, Skeletal; Mutation
PubMed: 36529094
DOI: 10.1016/j.coph.2022.102330 -
The Journal of Clinical Investigation Jan 2023This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca2+) is a requisite second messenger... (Review)
Review
This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca2+) is a requisite second messenger in all living organisms. From C. elegans to mammals, Ca2+ is necessary for locomotion, bodily functions, and neural activity. However, too much of a good thing can be bad. Intracellular Ca2+ overload can result in loss of function and death. Intracellular Ca2+ release channels evolved to safely provide large, rapid Ca2+ signals without exposure to toxic extracellular Ca2+. RyRs are intracellular Ca2+ release channels present throughout the zoosphere. Over the past 35 years, our knowledge of RyRs has advanced to the level of atomic-resolution structures revealing their role in the mechanisms underlying the pathogenesis of human disorders of heart, muscle, and brain. Stress-induced RyR-mediated intracellular Ca2+ leak in the heart can promote heart failure and cardiac arrhythmias. In skeletal muscle, RyR1 leak contributes to muscle weakness in inherited myopathies, to age-related loss of muscle function and cancer-associated muscle weakness, and to impaired muscle function in muscular dystrophies, including Duchenne. In the brain, leaky RyR channels contribute to cognitive dysfunction in Alzheimer's disease, posttraumatic stress disorder, and Huntington's disease. Novel therapeutics targeting dysfunctional RyRs are showing promise.
Topics: Humans; Calcium; Muscle Weakness; Muscle, Skeletal; Ryanodine Receptor Calcium Release Channel
PubMed: 36647824
DOI: 10.1172/JCI162891 -
Circulation May 2022Exercise training, and catecholaminergic stimulation, increase the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular...
BACKGROUND
Exercise training, and catecholaminergic stimulation, increase the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy correlated with plakophilin-2 (PKP2) mutations. Separate data show that reduced abundance of PKP2 leads to dysregulation of intracellular Ca (Ca) homeostasis. Here, we study the relation between excercise, catecholaminergic stimulation, Ca homeostasis, and arrhythmogenesis in PKP2-deficient murine hearts.
METHODS
Experiments were performed in myocytes from a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout murine line (PKP2cKO). For training, mice underwent 75 minutes of treadmill running once per day, 5 days each week for 6 weeks. We used multiple approaches including imaging, high-resolution mass spectrometry, electrocardiography, and pharmacological challenges to study the functional properties of cells/hearts in vitro and in vivo.
RESULTS
In myocytes from PKP2cKO animals, training increased sarcoplasmic reticulum Ca load, increased the frequency and amplitude of spontaneous ryanodine receptor (ryanodine receptor 2)-mediated Ca release events (sparks), and changed the time course of sarcomeric shortening. Phosphoproteomics analysis revealed that training led to hyperphosphorylation of phospholamban in residues 16 and 17, suggesting a catecholaminergic component. Isoproterenol-induced increase in Ca transient amplitude showed a differential response to β-adrenergic blockade that depended on the purported ability of the blockers to reach intracellular receptors. Additional experiments showed significant reduction of isoproterenol-induced Ca sparks and ventricular arrhythmias in PKP2cKO hearts exposed to an experimental blocker of ryanodine receptor 2 channels.
CONCLUSIONS
Exercise disproportionately affects Ca homeostasis in PKP2-deficient hearts in a manner facilitated by stimulation of intracellular β-adrenergic receptors and hyperphosphorylation of phospholamban. These cellular changes create a proarrhythmogenic state that can be mitigated by ryanodine receptor 2 blockade. Our data unveil an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of PKP2 deficit. We suggest that membrane-permeable β-blockers are potentially more efficient for patients with arrhythmogenic right ventricular cardiomyopathy, highlight the potential for ryanodine receptor 2 channel blockers as treatment for the control of heart rhythm in the population at risk, and propose that PKP2-dependent and phospholamban-dependent arrhythmogenic right ventricular cardiomyopathy-related arrhythmias have a common mechanism.
Topics: Animals; Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Calcium; Calcium Signaling; Humans; Isoproterenol; Mice; Mice, Knockout; Myocytes, Cardiac; Physical Conditioning, Animal; Plakophilins; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 35491884
DOI: 10.1161/CIRCULATIONAHA.121.057757 -
Acta Myologica : Myopathies and... Dec 2020Congenital myopathies represent a clinically and genetically heterogeneous group of early-onset neuromuscular diseases with characteristic, but not always specific,... (Review)
Review
Congenital myopathies represent a clinically and genetically heterogeneous group of early-onset neuromuscular diseases with characteristic, but not always specific, histopathological features, often presenting with stable and/or slowly progressive truncal and proximal weakness. It is often not possible to have a diagnosis on clinical ground alone. Additional extraocular, respiratory, distal involvement, scoliosis, and distal laxity may provide clues. The "core myopathies" collectively represent the most common form of congenital myopathies, and the name pathologically corresponds to histochemical appearance of focally reduced oxidative enzyme activity and myofibrillar changes on ultrastructural studies. Because of the clinical, pathological, and molecular overlaps, central core disease and multiminicore disease will be discussed together.
Topics: Humans; Myopathies, Structural, Congenital; Myopathy, Central Core; Ophthalmoplegia; Ryanodine Receptor Calcium Release Channel
PubMed: 33458581
DOI: 10.36185/2532-1900-029 -
Cardiovascular Research Mar 2023Calcium-handling capacity is a major gauge of cardiomyocyte maturity. Ryanodine receptor 2 (RYR2) is the pre-dominant calcium channel that releases calcium from the...
AIMS
Calcium-handling capacity is a major gauge of cardiomyocyte maturity. Ryanodine receptor 2 (RYR2) is the pre-dominant calcium channel that releases calcium from the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) to activate cardiomyocyte contraction. Although RYR2 was previously implied as a key regulator of cardiomyocyte maturation, the mechanisms remain unclear. The aim of this study is to solve this problem.
METHODS AND RESULTS
We performed Cas9/AAV9-mediated somatic mutagenesis to knockout RYR2 specifically in cardiomyocytes in mice. We conducted a genetic mosaic analysis to dissect the cell-autonomous function of RYR2 during cardiomyocyte maturation. We found that RYR2 depletion triggered ultrastructural and transcriptomic defects relevant to cardiomyocyte maturation. These phenotypes were associated with the drastic activation of ER stress pathways. The ER stress alleviator tauroursodeoxycholic acid partially rescued the defects in RYR2-depleted cardiomyocytes. Overexpression of ATF4, a key ER stress transcription factor, recapitulated defects in RYR2-depleted cells. Integrative analysis of RNA-Seq and bioChIP-Seq data revealed that protein biosynthesis-related genes are the major direct downstream targets of ATF4.
CONCLUSION
RYR2-regulated ER homeostasis is essential for cardiomyocyte maturation. Severe ER stress perturbs cardiomyocyte maturation primarily through ATF4 activation. The major downstream effector genes of ATF4 are related to protein biosynthesis.
Topics: Animals; Mice; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel; Calcium; Sarcoplasmic Reticulum; Unfolded Protein Response; Calcium Signaling
PubMed: 35576474
DOI: 10.1093/cvr/cvac077 -
Archives of Insect Biochemistry and... Nov 2019Phylogenetic tree of the ryanodine receptor (RyR) family based on maximum likelihood estimation. (Review)
Review
Phylogenetic tree of the ryanodine receptor (RyR) family based on maximum likelihood estimation.
Topics: Alternative Splicing; Animals; Calcium; Homeostasis; Insect Proteins; Insecta; Phylogeny; RNA; Ryanodine Receptor Calcium Release Channel
PubMed: 31218747
DOI: 10.1002/arch.21590 -
The Journal of Eukaryotic Microbiology Sep 2022A Paramecium cell has as many types of membrane interactions as mammalian cells, as established with monoclonal antibodies by R. Allen and A. Fok. Since then, we have... (Review)
Review
A Paramecium cell has as many types of membrane interactions as mammalian cells, as established with monoclonal antibodies by R. Allen and A. Fok. Since then, we have identified key players, such as SNARE proteins, Ca -regulating proteins, including Ca -channels, Ca -pumps, Ca -binding proteins of different affinity, etc., at the molecular level, probed their function and localized them at the light and electron microscopy level. SNARE proteins, in conjunction with a synaptotagmin-like Ca -sensor protein, mediate membrane fusion. This interaction is additionally regulated by monomeric GTPases whose spectrum in Tetrahymena and Paramecium has been established by A. Turkewitz. As known from mammalian cells, GTPases are activated on membranes in conjunction with lumenal acidification by an H -ATPase. For these complex molecules, we found in Paramecium an unsurpassed number of 17 a-subunit paralogs which connect the polymeric head and basis part, V1 and V0. (This multitude may reflect different local functional requirements.) Together with plasmalemmal Ca -influx channels, locally enriched intracellular InsP -type (InsP R, mainly in osmoregulatory system) and ryanodine receptor-like Ca -release channels (ryanodine receptor-like proteins, RyR-LP), this complexity mediates Ca signals for most flexible local membrane-to-membrane interactions. As we found, the latter channel types miss a substantial portion of the N-terminal part. Caffeine and 4-chloro-meta-cresol (the agent used to probe mutations of RyRs in man during surgery in malignant insomnia patients) initiate trichocyst exocytosis by activating Ca -release channels type CRC-IV in the peripheral part of alveolar sacs. This is superimposed by Ca -influx, that is, a mechanism called "store-operated Ca -entry" (SOCE). For the majority of key players, we have mapped paralogs throughout the Paramecium cell, with features in common or at variance in the different organelles participating in vesicle trafficking. Local values of free Ca -concentration, [Ca ] , and their change, for example, upon exocytosis stimulation, have been registered by flurochromes and chelator effects. In parallel, we have registered release of Ca from alveolar sacs by quenched-flow analysis combined with cryofixation and X-ray microanalysis.
Topics: Animals; Calcium; Calcium Signaling; Cell Membrane; GTP Phosphohydrolases; Humans; Mammals; Paramecium; Ryanodine Receptor Calcium Release Channel; SNARE Proteins
PubMed: 35156735
DOI: 10.1111/jeu.12895 -
Skeletal Muscle Nov 2020The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1... (Review)
Review
The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.Historically, RYR1-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1-RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (RYR1- [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1-related disorders (RYR1-RD) as a unified nomenclature to describe this complex and evolving disease spectrum.
Topics: Animals; Humans; Neuromuscular Diseases; Phenotype; Ryanodine Receptor Calcium Release Channel; Terminology as Topic
PubMed: 33190635
DOI: 10.1186/s13395-020-00243-4