scholarly journals Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts

2016 ◽  
Vol 473 (21) ◽  
pp. 3951-3964 ◽  
Author(s):  
Xiaowei Zhong ◽  
Bo Sun ◽  
Alexander Vallmitjana ◽  
Tao Mi ◽  
Wenting Guo ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Important Determinant ◽  
Polymorphic Ventricular Tachycardia ◽  
Release Channel ◽  
Cardiac Alternans ◽  
Β Blocker ◽  
Opposite Manner ◽  
Electrocardiogram Ecg

Beat-to-beat alternations in the amplitude of the cytosolic Ca2+ transient (Ca2+ alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca2+ alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca2+ release channel responsible for cytosolic Ca2+ transients, in cardiac alternans. Using a unique mouse model harboring a suppression-of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca2+ and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo. We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca2+ release refractoriness and enhanced propensity for Ca2+ alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca2+ alternans in RyR2-SOF hearts, whereas carvedilol, a β-blocker that suppresses RyR2 activity and CPVT, promoted Ca2+ alternans in these hearts. Thus, RyR2 function is an important determinant of Ca2+, APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.

Neurofilament phosphorylation

1995 ◽  
Vol 73 (9-10) ◽  
pp. 575-592 ◽  
Author(s):  
Harish C. Pant ◽  
Veeranna
Keyword(s):  
Molecular Weight ◽  
Nervous System ◽  
Nervous Tissue ◽  
Important Determinant ◽  
Neurofilament Proteins ◽  
Neurofilament Phosphorylation ◽  
Axonal Compartment

Neurofilament proteins (NFPs) are highly phosphorylated molecules in the axonal compartment of the adult nervous system. The phosphorylation of NFP is considered an important determinant of filament caliber, plasticity, and stability. This process reflects the function of NFs during the lifetime of a neuron from differentiation in the embryo through long-term activity in the adult until aging and environmental insult leads to pathology and ultimately death. NF function is modulated by phosphorylation–dephosphorylation in each of these diverse neuronal states. In this review, we have summarized some of these properties of NFP in adult nervous tissue, mostly from work in our own laboratory. Identification of sites phosphorylated in vivo in high molecular weight NFP (NF-H) and properties of NF-associated and neural-specific kinases phosphorylating specific sites in NFP are described. A model to explain the role of NF phosphorylation in determining filament caliber, plasticity, and stability is proposed.Key words: neurofilament proteins, phosphorylation, kinases, phosphatases, regulators, inhibitors, multimesic complex, domains.

scholarly journals Role of Amino-terminal Half of the S4-S5 Linker in Type 1 Ryanodine Receptor (RyR1) Channel Gating

2011 ◽  
Vol 286 (41) ◽  
pp. 35571-35577 ◽  
Author(s):  
Takashi Murayama ◽  
Nagomi Kurebayashi ◽  
Toshiharu Oba ◽  
Hideto Oyamada ◽  
Katsuji Oguchi ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Single Channel ◽  
Signal Transmission ◽  
Channel Gating ◽  
Helical Structure ◽  
Release Channel ◽  
Amino Terminal ◽  
Molecular Events

The type 1 ryanodine receptor (RyR1) is a Ca2+ release channel found in the sarcoplasmic reticulum of skeletal muscle and plays a pivotal role in excitation-contraction coupling. The RyR1 channel is activated by a conformational change of the dihydropyridine receptor upon depolarization of the transverse tubule, or by Ca2+ itself, i.e. Ca2+-induced Ca2+ release (CICR). The molecular events transmitting such signals to the ion gate of the channel are unknown. The S4-S5 linker, a cytosolic loop connecting the S4 and S5 transmembrane segments in six-transmembrane type channels, forms an α-helical structure and mediates signal transmission in a wide variety of channels. To address the role of the S4-S5 linker in RyR1 channel gating, we performed alanine substitution scan of N-terminal half of the putative S4-S5 linker (Thr4825–Ser4829) that exhibits high helix probability. The mutant RyR1 was expressed in HEK cells, and CICR activity was investigated by caffeine-induced Ca2+ release, single-channel current recordings, and [3H]ryanodine binding. Four mutants (T4825A, I4826A, S4828A, and S4829A) had reduced CICR activity without changing Ca2+ sensitivity, whereas the L4827A mutant formed a constitutive active channel. T4825I, a disease-associated mutation for malignant hyperthermia, exhibited enhanced CICR activity. An α-helical wheel representation of the N-terminal S4-S5 linker provides a rational explanation to the observed activities of the mutants. These results suggest that N-terminal half of the S4-S5 linker may form an α-helical structure and play an important role in RyR1 channel gating.

scholarly journals Ryanodine Receptor 1-mediated Ca2+ signaling and mitochondrial reprogramming modulate uterine serous cancer malignant phenotypes

2021 ◽  
Author(s):  
Li Zhang ◽  
Chunxian Huang ◽  
Tsz-Lun Yeung ◽  
Sammy Ferri-Borgogno ◽  
Chilam AuYeung ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Ryanodine Receptor ◽  
Functional Role ◽  
Patient Survival ◽  
Uterine Cancer ◽  
Atp Production ◽  
Ryanodine Receptor 1

Abstract Background Uterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker RYR1 identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment. Methods TCGA USC dataset was analyzed to identify top genes that are associated with patient survival and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models. Results High expression level of ryanodine receptor 1 (RYR1) in the tumors is associated with shortened overall survival. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through the Ca2+-dependent AKT/CREB/PGC-1α and AKT/HK1/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression in both in vitro and mouse models. Conclusions These findings provide insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival.

Abstract 277: MicroRNA-125a-5p Protects the Mouse Heart From Ischemic Injury by Repressing Pro-apoptotic Bak1 and Klf13 in Cardiomyocytes

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Bruno Moukette ◽  
Tatsuya Aonuma ◽  
Il-man Kim
Keyword(s):  
Target Genes ◽  
Cardiac Injury ◽  
Cell Types ◽  
Mouse Heart ◽  
Small Noncoding Rnas ◽  
Increased Sensitivity ◽  
Β Blocker ◽  
Apoptotic Genes

Background: Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs), which are small noncoding RNAs to downregulate target genes. MiR-125a-5p (miR-125a) is downregulated in patients with myocardial infarction (MI). We reported that miR-125a is upregulated by the β-blocker carvedilol (Carv) acting through β-arrestin1-biased β1-adrenergic receptor (β1AR; receptor found mainly in cardiomyocytes [CMs]) cardioprotective signaling (Figure A). We also showed that pro-apoptotic genes bak1 and klf13 are downregulated by Carv and are upregulated after MI. Here, we hypothesize that miR-125a in CMs favorably regulates cardiac functional and structural remodeling after MI by repressing bak1 and klf13. Methods and Results: Fractionation of cardiac cell types from heart tissues reveals that the expression of miR-125a is higher in CMs than other myocardial cells. Using cultured CM and in vivo approaches, we show that miR-125a is an ischemic stress-responsive protector against CM apoptosis. CMs lacking miR-125a exhibit an increased sensitivity to apoptosis, while CMs overexpressing miR-125a have increased phospho-AKT pro-survival signaling. Moreover, we show that miR-125a is downregulated in post-MI mouse hearts and miR-125a overexpression protects mouse hearts against MI. We also show that global genetic deletion of miR-125a in mice worsens maladaptive post-MI remodeling. Mechanistically, the cardioprotective role of miR-125a during MI is in part attributed to direct repression of the pro-apoptotic genes bak1 and klf13 in CMs (Figure B). Conclusions: These findings reveal a pivotal role for miR-125a in regulating CM survival during MI.

Evidence for a role of C-terminus in Ca2+ inactivation of skeletal muscle Ca2+ release channel (ryanodine receptor)

FEBS Letters ◽  
1999 ◽  
Vol 459 (2) ◽  
pp. 154-158 ◽  
Author(s):  
Junichi Nakai ◽  
Ling Gao ◽  
Le Xu ◽  
Chunlin Xin ◽  
Daniel A. Pasek ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Release Channel ◽  
C Terminus

scholarly journals Calmodulin sensitivity of the sarcoplasmic reticulum ryanodine receptor from normal and malignant-hyperthermia-susceptible muscle

1996 ◽  
Vol 319 (2) ◽  
pp. 421-426 ◽  
Author(s):  
Sean O'DRISCOLL ◽  
Tommie V. McCARTHY ◽  
Hans M. EICHINGER ◽  
Wolf ERHARDT ◽  
Frank LEHMANN-HORN ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Central Region ◽  
Dependent Manner ◽  
Release Channel ◽  
Malignant Hyperthermia Susceptible ◽  
Potential Binding ◽  
Cam Regulation

Ca2+ release from sarcoplasmic reticulum (SR) of malignant-hyperthermia-susceptible (MHS) muscle is hypersensitive to Ca2+ and caffeine. To determine if an abnormal calmodulin (CaM) regulation of the SR Ca2+-release-channel-ryanodine-receptor complex (RYR1) contributes to this hypersensitivity, we investigated the effect of CaM on high-affinity [3H]ryanodine binding to isolated SR vesicles from normal and MHS pig skeletal muscle. CaM modulated [3H]ryanodine binding in a Ca2+-dependent manner. In the presence of maximally activating Ca2+ concentrations, CaM inhibited [3H]ryanodine binding with no differences between normal and MHS vesicles. In the absence of Ca2+, however, CaM activated [3H]ryanodine binding with a 2-fold-higher potency in MHS vesicles. Significant differences between normal and MHS tissue were observed for CaM concentrations between 50 nM and 10 µM. A polyclonal antibody raised against the central region of RYR1 specifically inhibited this activating effect of CaM without affecting the inhibition by CaM. This indicates that the central region of RYR1 is a potential binding domain for CaM in the absence of Ca2+. It is suggested that in vivo an enhanced CaM sensitivity of RYR1 might contribute to the abnormal high release of Ca2+ from the SR of MHS muscle.

scholarly journals In vitro and in vivo replication of influenza A H1N1 WSN33 viruses with different M1 proteins

2013 ◽  
Vol 94 (4) ◽  
pp. 884-895 ◽  
Author(s):  
Zhiguang Ran ◽  
Ying Chen ◽  
Huigang Shen ◽  
Xiaoxiao Xiang ◽  
Qinfang Liu ◽  
...  
Keyword(s):  
Influenza A ◽  
Cultured Cells ◽  
Important Determinant ◽  
Clinical Manifestations ◽  
Structural Protein ◽  
M1 Protein ◽  
Influenza A H1n1

The M1 protein is a major structural protein that has multiple functions in various steps within the life cycle of the influenza A virus (IAV). However, little is currently known about the role of M1 in IAV replication in vivo and the associated pathogenesis. In this study, six isogenic H1N1 WSN33 viruses, constructed to express unique M1 proteins derived from various strains, subtypes or WSN33 itself, were tested to determine in vitro and in vivo functional exchangeability of M1 proteins in the replication and pathogenesis of the WSN33 virus. Despite five chimeric M1 viruses replicating to levels similar to those of the parental WSN33 virus in cell cultures, all M1 chimeras exhibited improved replication and enhanced virulence in mice when compared with the WSN33 virus. Interestingly, M1 proteins derived from swine viruses caused more severe clinical diseases than those from human or quail. These data indicate that the M1 protein is an important determinant of viral replication and pathogenic properties in mice, although the functions of M1 observed in vivo are not adequately reflected in simple infections of cultured cells. Chimeric M1 viruses that are variable in their clinical manifestations described here will aid future understanding of the role of M1 in IAV pathogenesis.

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