-
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 -
Neuromuscular Disorders : NMD Oct 2023Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in...
Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.
Topics: Animals; Humans; Acute Disease; Calcium; Malignant Hyperthermia; Mutation; Pancreatitis; Ryanodine Receptor Calcium Release Channel
PubMed: 37783627
DOI: 10.1016/j.nmd.2023.09.003 -
Nature Communications Jun 2024Calmodulin transduces [Ca] information regulating the rhythmic Ca cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac...
Calmodulin transduces [Ca] information regulating the rhythmic Ca cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac and skeletal muscle. However, the structural dynamics by which calmodulin modulates the sarcoplasmic reticulum Ca release channel, the ryanodine receptor, at physiologically relevant [Ca] is unknown. Using fluorescence lifetime FRET, we resolve different structural states of calmodulin and Ca-driven shifts in the conformation of calmodulin bound to ryanodine receptor. Skeletal and cardiac ryanodine receptor isoforms show different calmodulin-ryanodine receptor conformations, as well as binding and structural kinetics with 0.2-ms resolution, which reflect different functional roles of calmodulin. These FRET methods provide insight into the physiological calmodulin-ryanodine receptor structural states, revealing additional distinct structural states that complement cryo-EM models that are based on less physiological conditions. This technology will drive future studies on pathological calmodulin-ryanodine receptor interactions and dynamics with other important ryanodine receptor bound modulators.
Topics: Ryanodine Receptor Calcium Release Channel; Calmodulin; Calcium; Myocardium; Kinetics; Animals; Muscle, Skeletal; Fluorescence Resonance Energy Transfer; Humans; Protein Conformation; Protein Binding; Sarcoplasmic Reticulum
PubMed: 38879623
DOI: 10.1038/s41467-024-48951-5 -
European Journal of Pharmacology Sep 2014Ryanodine receptors are Ca(2+) release channels of internal stores. This review focuses on those situations and conditions that transform RyRs from a finely regulated... (Review)
Review
Ryanodine receptors are Ca(2+) release channels of internal stores. This review focuses on those situations and conditions that transform RyRs from a finely regulated ion channel to an unregulated Ca(2+) leak channel and the pathological consequences of this alteration. In skeletal muscle, mutations in either CaV1.1 channel or RyR1 results in a leaky behavior of the latter. In heart cells, RyR2 functions normally as a Ca(2+) leak channel during diastole within certain limits, the enhancement of this activity leads to arrhythmogenic situations that are tackled with different pharmacological strategies. In smooth muscle, RyRs are involved more in reducing excitability than in stimulating contraction so the leak activity of RyRs in the form of Ca(2+) sparks, locally activates Ca(2+)-dependent potassium channels to reduce excitability. In neurons the enhanced activity of RyRs is associated with the development of different neurodegenerative disorders such as Alzheimer and Huntington diseases. It appears then that the activity of RyRs as leak channels can have both physiological and pathological consequences depending on the cell type and the metabolic condition.
Topics: Animals; Calcium; Humans; Muscle, Skeletal; Myocardium; Myocytes, Smooth Muscle; Neurons; Ryanodine Receptor Calcium Release Channel
PubMed: 24291096
DOI: 10.1016/j.ejphar.2013.11.016 -
Biochemical Society Transactions Jun 2015The ryanodine receptor/Ca2+ release channel plays a pivotal role in skeletal and cardiac muscle excitation-contraction coupling. Defective regulation leads to... (Review)
Review
The ryanodine receptor/Ca2+ release channel plays a pivotal role in skeletal and cardiac muscle excitation-contraction coupling. Defective regulation leads to neuromuscular disorders and arrhythmogenic cardiac disease. This mini-review focuses on channel regulation through structural intra- and inter-subunit interactions and their implications in ryanodine receptor pathophysiology.
Topics: Calcium; Calcium Signaling; Heart Diseases; Humans; Muscle Contraction; Muscle, Skeletal; Myocardium; Neuromuscular Diseases; Protein Conformation; Protein Structure, Tertiary; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Structure-Activity Relationship
PubMed: 26009179
DOI: 10.1042/BST20140292 -
Anesthesiology Mar 2017
Topics: Anesthetics; Calcium; Calcium Channels; Heart; Humans; Myocardium; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum
PubMed: 28079565
DOI: 10.1097/ALN.0000000000001520 -
Science (New York, N.Y.) Aug 2016(+)-Ryanodine and (+)-ryanodol are complex diterpenoids that modulate intracellular calcium-ion release at ryanodine receptors, ion channels critical for skeletal and...
(+)-Ryanodine and (+)-ryanodol are complex diterpenoids that modulate intracellular calcium-ion release at ryanodine receptors, ion channels critical for skeletal and cardiac muscle excitation-contraction coupling and synaptic transmission. Chemical derivatization of these diterpenoids has demonstrated that certain peripheral structural modifications can alter binding affinity and selectivity among ryanodine receptor isoforms. Here, we report a short chemical synthesis of (+)-ryanodol that proceeds in only 15 steps from the commercially available terpene (S)-pulegone. The efficiency of the synthesis derives from the use of a Pauson-Khand reaction to rapidly build the carbon framework and a SeO2-mediated oxidation to install three oxygen atoms in a single step. This work highlights how strategic C-O bond constructions can streamline the synthesis of polyhydroxylated terpenes by minimizing protecting group and redox adjustments.
Topics: Biological Products; Cyclohexane Monoterpenes; Monoterpenes; Oxidation-Reduction; Oxygen; Ryanodine; Ryanodine Receptor Calcium Release Channel; Selenium Oxides
PubMed: 27563092
DOI: 10.1126/science.aag1028 -
Mini Reviews in Medicinal Chemistry 2019Ryanodine receptors (RyRs) are calcium channels located on the endo(sarco)plasmic reticulum of muscle cells and neurons. They regulate the release of stored... (Review)
Review
Ryanodine receptors (RyRs) are calcium channels located on the endo(sarco)plasmic reticulum of muscle cells and neurons. They regulate the release of stored intracellular calcium and play a critical role in muscle contraction. The N-terminal part of these receptors accounts for roughly 80% and contains the binding sites for diverse RyRs modulators. The C-terminal domain contains the transmembrane region. This review summarizes the current knowledge about the molecular biology of insect RyRs, chemicals targeting mammal or insect RyRs, and the reasons for mammal RyR-related diseases and diamides resistances. It may lay the foundation for effective management of mammal RyR-related diseases and diamides resistances.
Topics: Animals; Diamide; Drug Discovery; Humans; Insect Control; Insecta; Insecticide Resistance; Insecticides; Ryanodine; Ryanodine Receptor Calcium Release Channel
PubMed: 29600763
DOI: 10.2174/1389557518666180330112908 -
Biochimica Et Biophysica Acta Jun 2016Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca(2+) mobilizing second messenger that belongs to the superfamily of regulatory adenine nucleotides. Though... (Review)
Review
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca(2+) mobilizing second messenger that belongs to the superfamily of regulatory adenine nucleotides. Though NAADP has been known since 20 years, several aspects of its metabolism and molecular mode of action are still under discussion. Though the importance of the type 1 ryanodine receptor was discovered and published already in 2002 Hohenegger et al. (2002 Oct 15), recent data re-emphasize these original findings in pancreatic acinar cells and in T-lymphocytes. Here we review recent developments in NAADP formation and metabolism, putative target Ca(2+) channels for NAADP with special emphasis on the type 1 ryanodine receptor, and NAADP binding proteins. The latter are basis for a unifying hypothesis for NAADP action. Finally, the role of NAADP in T cell Ca(2+) signaling and activation is discussed. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.
Topics: Animals; Calcium; Calcium Signaling; Humans; Lymphocyte Activation; Membrane Microdomains; Models, Biological; NADP; Ryanodine Receptor Calcium Release Channel; T-Lymphocytes
PubMed: 26804481
DOI: 10.1016/j.bbamcr.2016.01.014 -
CNS & Neurological Disorders Drug... 2019Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for Malignant Hyperthermia (MH). Inhibition of... (Review)
Review
Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for Malignant Hyperthermia (MH). Inhibition of Ryanodine Receptor (RyR) by dantrolene decreases the abnormal calcium release from the Sarcoplasmic Reticulum (SR) or Endoplasmic Reticulum (ER), where RyR is located. Recently, emerging researches on dissociated cells, brains slices, live animal models and patients have demonstrated that altered RyR expression and function can also play a vital role in the pathogenesis of Alzheimer's Disease (AD). Therefore, dantrolene is now widely studied as a novel treatment for AD, targeting the blockade of RyR channels or another alternative pathway, such as the inhibitory effects of NMDA glutamate receptors and the effects of ER-mitochondria connection. However, the therapeutic effects are not consistent. In this review, we focus on the relationship between the altered RyR expression and function and the pathogenesis of AD, and the potential application of dantrolene as a novel treatment for the disease.
Topics: Alzheimer Disease; Animals; Calcium; Dantrolene; Humans; Malignant Hyperthermia; Muscle, Skeletal; Ryanodine Receptor Calcium Release Channel
PubMed: 29921212
DOI: 10.2174/1871527317666180619162649