The Ryanodine Receptor as a Sensor for Intracellular Environments in Muscles.
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ABSTRACT:
SUBMITTER: Kobayashi T
PROVIDER: S-EPMC8509754 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ca2+ regulates ryanodine receptor's (RyR) activity through an activating and an inhibiting Ca2+-binding site located on the cytoplasmic side of the RyR channel. Their altered sensitivity plays an important role in the pathology of malignant hyperthermia and heart failure. We used lanthanide ions (Ln3+) as probes to investigate the Ca2+ sensors of RyR, because they specifically bind to Ca2+-binding proteins and they are impermeable to the channel. Eu3+'s and Sm3+'s action was tested on single RyR1 channels reconstituted into planar lipid bilayers. When the activating binding site was saturated by 50 ?M Ca2+, Ln3+ potently inhibited RyR's open probability (Kd Eu3+ = 167 ± 5 nM and Kd Sm3+ = 63 ± 3 nM), but in nominally 0 [Ca2+], low [Eu3+] activated the channel. These results suggest that Ln3+ acts as an agonist of both Ca2+-binding sites. More importantly, the voltage-dependent characteristics of Ln3+'s action led to the conclusion that the activating Ca2+ binding site is located within the electrical field of the channel (in the vestibule). This idea was tested by applying the pore blocker toxin maurocalcine on the cytoplasmic side of RyR. These experiments showed that RyR lost reactivity to changing cytosolic [Ca2+] from 50 ?M to 100 nM when the toxin occupied the vestibule. These results suggest that maurocalcine mechanically prevented Ca2+ from dissociating from its binding site and support our vestibular Ca2+ sensor-model further.
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Project description:Investigate the function of RNLs in transcriptional reprogramming during Pf0-1-induced PTI and ETI, using time-resolved transcriptomics. To do so we subjected Col-0, adr1 triple, nrg1.1 nrg1.2 and helperless mutants to infections with Pf0-EV (RNL-(in)dependent PTI), Pf0-AvrRps4 (fully RNL-dependent ETI + PTI), Pf0-AvrRpt2 (partial RNL-dependent ETI + PTI) or Pf0-AvrRpm1 (RNL-independent ETI + PTI).
2020-06-22 | GSE151885 | GEO
Project description:Activation of intracellular Ca(2+)-release channels/ryanodine receptors (RyRs) is a fundamental step in the regulation of muscle contraction. In mammalian skeletal muscle, Ca(2+)-release channels containing the type 1 isoform of RyR (RyR1) open to release Ca2+ from the sarcoplasmic reticulum (SR) upon stimulation by the voltage-activated dihydropyridine receptor on the T-tubule/plasma membrane. In addition to RyR1, low levels of the mRNA of the RyR3 isoform have been recently detected in mammalian skeletal muscles. Here we report data on the distribution of the RyR3 gene product in mammalian skeletal muscles. Western-blot analysis of SR of individual muscles indicated that, at variance with the even distribution of the RyR1 isoform, the RyR3 content varies among different muscles, with relatively higher amounts being detected in diaphragm and soleus, and lower levels in abdominal muscles and tibialis anterior. In these muscles RyR3 was localized in the terminal cisternae of the SR. No detectable levels of RyR3 were observed in the extensor digitorum longus. Preferential high content of RyR3 in the diaphragm muscle was observed in several mammalian species. In situ hybridization analysis demonstrated that RyR3 transcripts are not restricted to a specific subset of skeletal-muscle fibres. Differential utilization of the RyR3 isoform in skeletal muscle may be relevant to the modulation of Ca2+ release with respect to specific muscle-contraction properties.
| S-EPMC1217321 | biostudies-other
Project description:Recent studies have identified Ca(2+) stores in sperm cells; however, it is not clear whether these Ca(2+) stores are functional and how they are mobilized. Here, in vitro and in vivo, we determined that tripeptidyl peptidase II antagonists strongly activated the cAMP/PKA signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation. We demonstrated that in the absence of Ca(2+), TPIII antagonists elevated the intracellular Ca(2+) levels in sperm, resulting in a marked improvement in sperm movement, capacitation, acrosome reaction, and the in vitro fertilizing ability. This antagonist-induced release of intracellular Ca(2+) could be blocked by the inhibitors of ryanodine receptors (RyRs) which are the main intracellular Ca(2+) channels responsible for releasing stored Ca(2+). Consistent with these results, indirect immunofluorescence assay using anti-RyR antibodies further validated the presence of RyR3 in the acrosomal region of mature sperm. Thus, TPPII can regulate sperm maturation by modulating intracellular Ca(2+) stores via the type 3 RyR.
| S-EPMC3688596 | biostudies-literature
Project description:Age-related loss of muscle mass and force (sarcopenia) contributes to disability and increased mortality. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium release channel required for muscle contraction. RyR1 from aged (24 months) rodents was oxidized, cysteine-nitrosylated, and depleted of the channel-stabilizing subunit calstabin1, compared to RyR1 from younger (3-6 months) adults. This RyR1 channel complex remodeling resulted in "leaky" channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice. Treating aged mice with S107 stabilized binding of calstabin1 to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species (ROS), and enhanced tetanic Ca(2+) release, muscle-specific force, and exercise capacity. Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function.
| S-EPMC3690519 | biostudies-other
Project description:Plant nucleotide-binding (NB) leucine-rich repeat (LRR) receptor (NLR) proteins function as intracellular immune receptors that perceive the presence of pathogen-derived virulence proteins (effectors) to induce immune responses. The 2 major types of plant NLRs that "sense" pathogen effectors differ in their N-terminal domains: these are Toll/interleukin-1 receptor resistance (TIR) domain-containing NLRs (TNLs) and coiled-coil (CC) domain-containing NLRs (CNLs). In many angiosperms, the RESISTANCE TO POWDERY MILDEW 8 (RPW8)-CC domain containing NLR (RNL) subclass of CNLs is encoded by 2 gene families, ACTIVATED DISEASE RESISTANCE 1 (ADR1) and N REQUIREMENT GENE 1 (NRG1), that act as "helper" NLRs during multiple sensor NLR-mediated immune responses. Despite their important role in sensor NLR-mediated immunity, knowledge of the specific, redundant, and synergistic functions of helper RNLs is limited. We demonstrate that the ADR1 and NRG1 families act in an unequally redundant manner in basal resistance, effector-triggered immunity (ETI) and regulation of defense gene expression. We define RNL redundancy in ETI conferred by some TNLs and in basal resistance against virulent pathogens. We demonstrate that, in Arabidopsis thaliana, the 2 RNL families contribute specific functions in ETI initiated by specific CNLs and TNLs. Time-resolved whole genome expression profiling revealed that RNLs and "classical" CNLs trigger similar transcriptome changes, suggesting that RNLs act like other CNLs to mediate ETI downstream of sensor NLR activation. Together, our genetic data confirm that RNLs contribute to basal resistance, are fully required for TNL signaling, and can also support defense activation during CNL-mediated ETI.
| S-EPMC7514072 | biostudies-literature
Project description:Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and quality of life. Although, ryanodine receptor type 2 (RyR2) has been linked to cardiac muscle dysfunction, its role in CD remains unclear. Here, we show in hippocampal neurons from patients and mice with HF that the ryanodine receptor type 2 (RyR2)/intracellular Ca 2+ release channels were post-translationally modified (PTM) and leaky. RyR2 PTM was caused by hyper-adrenergic stress and activation of the transforming growth factor (TGF-β) pathway. HF mice treated with either a RyR2 stabilizer drug (S107), beta-blocker (propranolol) or TGF-β inhibitor (SD-208), or mice insensitive RyR2 Ca 2+ leak (RyR2-S2808A), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness that include cardiogenic dementia, and intracellular Ca 2+ leak is a common effector in multiple components of HF.
2023-08-30 | PXD042295 | Pride
Project description:CASQ2 (cardiac calsequestrin) is commonly believed to serve as the SR (sarcoplasmic reticulum) luminal Ca2+ sensor. Ablation of CASQ2 promotes SCWs (spontaneous Ca2+ waves) and CPVT (catecholaminergic polymorphic ventricular tachycardia) upon stress but not at rest. How SCWs and CPVT are triggered by stress in the absence of the CASQ2-based luminal Ca2+ sensor is an important unresolved question. In the present study, we assessed the role of the newly identified RyR2 (ryanodine receptor 2)-resident luminal Ca2+ sensor in determining SCW propensity, CPVT susceptibility and cardiac hypertrophy in Casq2-KO (knockout) mice. We crossbred Casq2-KO mice with RyR2 mutant (E4872Q+/-) mice, which lack RyR2-resident SR luminal Ca2+ sensing, to generate animals with both deficiencies. Casq2+/- and Casq2-/- mice showed stress-induced VTs (ventricular tachyarrhythmias), whereas Casq2+/-/E4872Q+/- and Casq2-/-/E4872Q+/- mice displayed little or no stress-induced VTs. Confocal Ca2+ imaging revealed that Casq2-/- hearts frequently exhibited SCWs after extracellular Ca2+ elevation or adrenergic stimulation, whereas Casq2-/-/E4872Q+/- hearts had few or no SCWs under the same conditions. Cardiac hypertrophy developed and CPVT susceptibility increased with age in Casq2-/- mice, but not in Casq2-/-/E4872Q+/- mice. However, the amplitudes and dynamics of voltage-induced Ca2+ transients in Casq2-/- and Casq2-/-/E4872Q+/- hearts were not significantly different. Our results indicate that SCWs, CPVT and hypertrophy in Casq2-null cardiac muscle are governed by the RyR2-resident luminal Ca2+ sensor. This implies that defects in CASQ2-based lumi-nal Ca2+ sensing can be overridden by the RyR2-resident luminal Ca2+ sensor. This makes this RyR2-resident sensor a promising molecular target for the treatment of Ca2+-mediated arrhythmias.
| S-EPMC4277184 | biostudies-literature
Project description:INTRODUCTION:Because impaired excitation-contraction coupling and reduced sarcoplasmic reticulum (SR) Ca2+ release may contribute to the age-associated decline in skeletal muscle strength, we investigated the effect of aging on regulation of the skeletal muscle isoform of the ryanodine receptor (RyR1) by physiological channel ligands. METHODS:[3 H]Ryanodine binding to membranes from 8- and 26-month-old Fischer 344 extensor digitorum longus (EDL) and soleus muscles was used to investigate the effects of age on RyR1 modulation by Ca2+ and calmodulin (CaM). RESULTS:Aging reduced maximal Ca2+ -stimulated binding to EDL membranes. In 0.3 ?M Ca2+ , age reduced binding and CaM increased binding to EDL membranes. In 300 ?M Ca2+ , CaM reduced binding, but the age effect was not significant. Aging did not affect Ca2+ or CaM regulation of soleus RyR1. DISCUSSION:In aged fast-twitch muscle, impaired RyR1 Ca2+ regulation may contribute to lower SR Ca2+ release and reduced muscle function. Muscle Nerve 57: 1022-1025, 2018.
| S-EPMC5951731 | biostudies-literature
Project description:Ryanodine receptors (RyRs) mediate the rapid release of calcium (Ca(2+)) from intracellular stores into the cytosol, which is essential for numerous cellular functions including excitation-contraction coupling in muscle. Lack of sufficient structural detail has impeded understanding of RyR gating and regulation. Here we report the closed-state structure of the 2.3-megadalton complex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle electron cryomicroscopy at an overall resolution of 4.8 Å. We fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca(2+).
| S-EPMC4300236 | biostudies-literature