Background: The molecular basis of calcium release by ryanodine receptors (RyRs) is incompletely understood. Results: Mutations predicted by a computational model alter Ca 2ϩ -dependent single RyR channel activity. Conclusion: An interface between a pore-lining helix and a linker helix has a critical role in RyR channel gating. Significance: The results provide new insights into how RyR activity is regulated by Ca 2ϩ .
BackgroundThis study was designed to research the potential function of lncRNA ANRIL in osteosarcoma (OS).Materials and methodsQuantitative real-time PCR, cell counting kit-8, wound healing assay, Transwell assay, flow cytometric analysis, caspase activity analysis, and Western blot were carried out.ResultsANRIL was remarkably upregulated in human OS tissues and cells, and knockdown of ANRIL significantly suppressed MG63 cell proliferation, migration, and invasion and promoted apoptosis. Moreover, our mechanistic research findings verified that ANRIL-influenced growth and apoptosis may be partly through regulation of caspase-3 and Bcl-2. Migration and invasion were influenced via ANRIL-mediated regulation of MTA1, TIMP-2, and E-cadherin.ConclusionOur finding demonstrates that ANRIL plays vital roles in OS growth and metastasis.
, a major active component of ginseng, has many benefits for cardiovascular disease and diabetes mellitus (DM), but the effect and mechanism on diabetic cardiomyopathy are not clear. In the present study, we found that Rb1-feeding significantly improved cardiac dysfunction and abnormal cardiomyocytes calcium signaling caused by diabetes. This improved calcium signaling was because Rb1 reduced Ca 2+ leakage caused by overactivated ryanodine receptor 2 (RyR2) and increased Ca 2+ uptake by sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA 2a). Furthermore, we found that Rb1 not only enhanced energy metabolism like metformin and eliminated O-GlcNAcylation of calcium handling proteins to regulate calcium signaling but also directly inhibited RyR2 activity to regulate calcium signaling. The present study indicated that as a health supplement or drug, Rb1 was a relatively effective auxiliary therapeutic substance for diabetic cardiomyopathy.
Activation of the skeletal muscle ryanodine receptor (RyR1) complex results in the rapid release of Ca2+ from the sarcoplasmic reticulum and muscle contraction. Dissociation of the small FK506 binding protein 12 subunit (FKBP12) increases RyR1 activity and impairs muscle function. The 1,4-benzothiazepine derivative JTV519, and the more specific derivative S107 (2,3,4,5,-tetrahydro-7-methoxy-4-methyl-1,4-benzothiazepine), are thought to improve skeletal muscle function by stabilizing the RyR1-FKBP12 complex. Here, we report a high degree of nonspecific and specific low affinity [3H]S107 binding to SR vesicles. SR vesicles enriched in RyR1 bound ∼48 [3H]S107 per RyR1 tetramer with EC50 ∼52 µM and Hillslope ∼2. The effects of S107 and FKBP12 on RyR1 were examined under conditions that altered the redox state of RyR1. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathione and the NO-donor NOC12, with no effect in the presence of oxidized glutathione. Addition of 0.15 µM FKBP12 to SR vesicles prevented FKBP12 dissociation; however, in the presence of oxidized glutathione and NOC12, FKBP12 dissociation was observed in skeletal muscle homogenates that contained 0.43 µM myoplasmic FKBP12 and was attenuated by S107. In single channel measurements with FKBP12-depleted RyR1s, in the absence and presence of NOC12, S107 augmented the FKBP12-mediated decrease in channel activity. The data suggest that S107 can reverse the harmful effects of redox active species on SR Ca2+ release in skeletal muscle by binding to RyR1 low affinity sites.
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