Ryanodine Receptor Research Articles

Introduction: Genetic mutations are a well-known cause of dilated cardiomyopathy (DCM), occurring in approximately 30% of the cases. Mutations in the ryanodine receptor 2 (RYR2) gene are shown to be associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Here, we present a rare case of a novel early nonsense mutation in the RYR2 gene associated with arrhythmogenic DCM. Case Description: A 44-year-old male patient who presented with exertional dyspnea and volume overload was found to be in new-onset decompensated heart failure secondary to non-ischemic cardiomyopathy. His telemetry monitoring showed continuous runs of non-sustained ventricular tachycardia. His ejection fraction (EF) was <10%, with global hypokinesis, biventricular dilation, and severely reduced right ventricular function. He rapidly decompensated into cardiogenic shock and was placed on inotropic support and an Impella 5.5. Cardiac magnetic resonance imaging revealed severe biventricular dilation and global hypokinesis without any left ventricular delayed enhancement, suggesting DCM with no evidence of ARVC. His genetic testing revealed a novel disease-causing mutation in the RYR2 gene, which caused a premature stop codon. The patient was diagnosed to have arrhythmogenic genetic dilated cardiomyopathy. Given the severity of his heart failure, the patient is currently being evaluated for an orthotopic heart transplant. Discussion: RYR2 is the major sarcoplasmic reticulum calcium release channel responsible for the excitation-contraction coupling of cardiac myocytes. RYR2 mutations are a known cause of CPVT and ARVC, but the literature on the occurrence of DCM in the setting of RYR2 gene mutation is scant. Studies have shown that Lamin A/C (LMNA) and the sodium channel alpha-subunit 5a (SCN5a) are the most commonly associated genes with arrhythmogenic DCM. This case highlights a unique unreported nonsense mutation in the RYR2 gene presenting as arrhythmogenic DCM. Given the occurrence of these rare mutations, further research efforts are needed to determine the significance of these novel mutations and their effect on future clinical outcomes and management of DCM. Once genetic cardiomyopathy is diagnosed, generational family screening should be considered. Patients should also be educated on their disease and the risks of familial transmission and provided with extensive genetic counseling.

Introduction: The role of β-adrenergic receptor (βAR) signaling in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. While β-blockers are effective in heart failure with reduced ejection fraction (HFrEF), they offer minimal benefit in HFpEF, suggesting disease-specific differences in adrenergic signaling. This study aims to investigate and compare subcellular adrenergic signaling in adult ventricular myocytes (AVMs) from mouse models of HFpEF and HFrEF. Methods: We analyzed RNA-seq data to assess βAR and downstream signaling gene expression in human HFpEF and HFrEF samples. To examine subcellular protein kinase A (PKA) activity, we developed FRET-based biosensors targeted to nanodomains at ryanodine receptor 2 (RyR2) and sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a). We evaluated local adrenergic-PKA signaling in AVMs isolated from HFpEF mice (induced by high-fat diet with L-NAME) and HFrEF mice (induced by chronic isoproterenol infusion). We further assessed calcium handling, contractility, and the effects of phosphodiesterase 4D (PDE4D) inhibition. Results: RNA-seq and Western blot analysis showed β1AR downregulation in human HFrEF and the isoproterenol-induced mouse HFrEF model (n=10), resulting in selective impairment of adrenergic-PKA signaling at RyR2 nanodomains. In contrast, β1AR expression remained unchanged in human HFpEF and HFD+L-NAME mouse hearts. However, PDE4D isoforms were upregulated and selectively associated with SERCA2a, leading to suppression of local adrenergic-PKA signaling (n=10). PDE4D inhibition rescued PKA activity specifically at the SERCA2a nanodomain, enhanced phospholamban phosphorylation, restored calcium cycling, and improved contractile function in HFpEF AVMs. In vivo, treatment with a PDE4 inhibitor ameliorated diastolic dysfunction in HFD+L-NAME mice (n=10). Conclusions: This study demonstrates distinct subcellular βAR-PKA signaling alterations in HFpEF versus HFrEF. While HFrEF is characterized by β1AR downregulation and RyR2 domain dysfunction, HFpEF shows preserved β1AR expression but increased PDE4D activity that impairs SERCA2a regulation. These findings identify PDE4D as a novel therapeutic target to restore localized adrenergic signaling and SERCA2a function in HFpEF.

Background: Calcium release channel deficiency syndrome (CRCDS) is caused by biogenic or biophysical loss-of-function (LOF) pathogenic variants in the RYR2 -encoded ryanodine receptor (RyR2), a key intracellular Ca 2+ release channel. Previously, we identified a novel homozygous duplication involving the promoter and exons 1-4 of RYR2 , leading to 80% RyR2 protein loss and exertion-related sudden death in the young. Here, we generated a RYR2 knockout (RYR2-KO) induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model to explore intracellular and electrophysiological compensatory mechanisms that overcome this extreme loss of RyR2 protein. Methods: Using CRISPR/Cas9 gene editing, a homozygous c.163delT variant (p.S55Pfs*46) was inserted into a normal iPSC line (isogenic control) to create a homozygous RYR2-KO iPSC line. After re-engineering the lines into ventricular-like cardiomyocytes (iPSC-CMs), intracellular Ca 2+ handling was assessed by Fluo-4 AM cell imaging (0.5 Hz stimulation). Electrical remodeling in the L-type Ca 2+ current (I CaL ) was assessed using the whole-cell patch clamp technique. Results: Significant differences were observed in Ca 2+ transient parameters between RYR2-KO and isogenic control iPSC-CMs. Biogenic RyR2 loss significantly reduced Ca 2+ transient peak amplitude (CTA: 0.16 ± 0.01 ΔF/F0, p<0.0001) and upstroke velocity (CTV: 0.42 ± 0.06 (ΔF/F0)/t, p<0.0001), and prolonged Ca 2+ transient duration (CTD 90 : 1.59 ± 0.03 s, p=0.01) as compared to isogenic control (CTA: 0.48 ± 0.04 ΔF/F0; CTV: 1.30 ± 0.15 (ΔF/F0)/t; CTD 90 : 1.46 ± 0.05 s). Additionally, RyR2 loss abolished SR Ca 2+ leak (0.9 ± 0.9 % versus 35.1 ± 15.5 %, p=0.03). Lastly, a significant reduction in I CaL density was observed in RYR2-KO iPSC-CMs as compared to isogenic control iPSC-CMs (at 0 mV, RYR2-KO: -8.54 ± 1.60 pA/pF, control: -17.45 ± 3.69 pA/pF, p=0.0004). These data indicate that I CaL reduction may contribute to the reduced Ca 2+ transient peak. Conclusions: Complete loss of RyR2 in iPSC-CMs profoundly disrupts intracellular Ca 2+ handling, abolishes Ca 2+ sparks frequency, and secondarily down-regulates the sarcolemmal L-type Ca 2+ channel.

IP3-mediated Ca2+ transfer from ER to mitochondria stimulates ATP synthesis in primary hippocampal neurons.

A systemically applied nanoparticle-based dsRNA biopesticide reduces Tuta absoluta survival.

Myotube-specific vulnerability to clozapine.

Defective assembly of primary cilia causes ciliopathies, but cilia disassembly and its role in disease remain poorly understood. From a genome-wide CRISPR activation (CRISPRa) screen for negative regulators of ciliary function, we find here that the F2R G protein–coupled receptor, sterile alpha and TIR motif-containing 1 (SARM1) hydrolase, ryanodine receptors, peri-centrosomal calcium signaling, and RhoA form a functional pathway that is necessary and sufficient for cilia disassembly. Highlighting the significance of this pathway, several components are somatically mutated in focal cortical dysplasia (FCD), a neurological disorder characterized by intractable epilepsy. Supporting the functional impact of these variants, patient-derived SARM1 and RhoA mutations potentiate cilia loss, and a RhoA variant impairs cortical development. Conversely, SARM1 inhibition restores cilia in cells with FCD-associated alterations. Together, our work identifies a pathway for cilia disassembly, implicates aberrant pathway activation as a feature of FCD-associated mutations, and illustrates the potential of CRISPRa screening to provide insight into diseases caused by somatic mutations.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused primarily by mutations in the gene encoding the methyl-CpG-binding protein 2 (Mecp2). Mecp2 binds to methylated cytosines, playing a crucial role in chromatin organization and transcriptional regulation. At the neurobiological level, RTT is characterized by dendritic spine dysgenesis and altered excitation–inhibition balance, drawing attention to the mechanisms that scale from mutations in a nuclear protein to altered neuronal connectivity. Although Mecp2 dysfunction disrupts multiple neuronal processes, emerging evidence highlights altered calcium (Ca2+) signaling as a central contributor to RTT pathophysiology. This review explores the link between Mecp2 and Ca2+ regulation by highlighting how Mecp2 affects Ca2+-dependent transcriptional pathways, while Ca2+ modulates Mecp2 function by inducing post-translational modifications. We discuss this crosstalk in light of evidence from RTT models, with a particular focus on the brain-derived neurotrophic factor BDNF-miR132-Mecp2 axis and the dysregulation of ryanodine receptors (RyRs). Additionally, we examine how these perturbations contribute to the reduced structural plasticity and the altered activity-driven gene expression that characterizes RTT. Understanding the intersection between Mecp2 function and Ca2+ homeostasis will provide critical insights into RTT pathogenesis and potential therapeutic targets aimed at restoring neuronal connectivity.

To explore the mechanism by which moxibustion promotes synaptic plasticity of hippocampal neurons and improves learning and memory in mice with Alzheimer's disease (AD) based on the calmodulin-dependent protein kinase Ⅱ (CaMKⅡ)/ryanodine receptor (RyR)3 pathway. Forty APP/PS1 mice were randomly divided into the model (n=15), moxibustion (n=25) groups, and 15 C57BL/6J mice served as the blank control group. The mice in the moxibustion group were given moxibustion at the "Baihui"(GV20) and "Yongquan"(KI1) acupoints, 30 minutes each time, once a day. A course of treatment lasted for 5 days, and there were a total of 4 courses of treatment. Ten mice from the moxibustion group were randomly selected as the moxibustion+inhibitor group, and were intraperitoneally injected with the CaMKⅡ protein inhibitor KN-93 (2 mg/100 g) one day before sample collection on the basis of moxibustion. After the treatment, the shuttle box test was used to evaluate the learning and memory ability of the mice. Transmission electron microscopy was used to detect the changes in the ultrastructure of synapses in the CA1 region of the hippocampus. Western blot was used to detect the expression levels of β-amyloid protein (Aβ) and CaMKⅡ protein in the hippocampus of the mice. Immunofluorescence staining was used to detect the positive expression of CaMKⅡ in the hippocampus and the co-expression of RyR3/PSD95. Compared with the blank control group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the percentage of the co-expression area of RyR3/PSD95 of the mice in the model group were decreased (P<0.01, P<0.05), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased;while the expression of Aβ protein in the hippocampus was increased (P<0.01). Compared with the model group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the co-expression area percentage of RyR3/PSD95 of the mice in the moxibustion group were increased significantly (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was increased;while the expression of Aβ protein was decreased (P<0.05). Compared with the moxibustion group, the number of active avoidance, the positive expression of CaMKⅡ and the co-expression area percentage of RyR3/PSD95 in the moxibustion+inhibitor group were decreased (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased. Moxibustion can improve the learning and memory ability of AD model mice, and its mechanism may be related to up-regulating the expression of CaMKⅡ, activating the endoplasmic reticulum RyR3 channel, inducing the release of Ca2+, and then promoting neuronal synaptic plasticity.

Background/Objectives: Variants in the RYR1 gene are associated mainly with Malignant Hyperthermia. Missense variants are largely the most common, while insertions and duplications account for less than 10%. We aimed to investigate the effect of a rare duplication in the RYR1 gene with the variability of the Malignant Hyperthermia susceptibility phenotype. Methods: We used exome variant screening, in vitro contracture test, anatomopathological examination of the muscle biopsy, RT-qPCR analysis for RYR1 relative expression. Results: We identified a family with two affected siblings carrying an insertion of 18 pair bases in exon 91 of the RYR1 gene, resulting in an in-frame duplication of 6 amino acids (c.12835_12852 dupGAGGGCGCGGCGGGGCTC: 162 p.G4279_T4284insAAGLEG). This variant was found at a frequency of 0.0007% in gnomAD and was absent in 1200 Brazilian controls. First classified as a Variant of Uncertain Significance (VUS), with the molecular and physiological data from our family, we were able to reclassify it, reaching 5 points, which is still a VUS but borderline likely pathogenic. Muscle relative mRNA expression of RYR1 in the two patients identified a ~50% reduction, suggesting a possible hypomorphic allele. Conclusions: The pathomechanisms of RYR1 gene variants in Malignant Hyperthermia are mainly associated with gain-of-function mechanisms, but small insertions can often lead to loss of function or improper folding protein. This study adds evidence to the possibility that duplication in this region can cause structural defects and a more severe phenotype in the patients.

Mitochondrial dysfunction caused by abnormally high RyR2 (ryanodine receptor) activity is a common finding in cardiovascular diseases. Mechanisms linking RyR2 gain of function with mitochondrial remodeling remain elusive. We hypothesized that RyR2 hyperactivity in cardiac disease increases [Ca2+] in the mitochondrial intermembrane space (IMS) and activates the Ca2+-sensitive protease calpain, driving remodeling of mitochondrial cristae architecture through cleavage of structural protein OPA1 (optic atrophy protein 1). We generated a highly arrhythmogenic rat model of catecholaminergic polymorphic ventricular tachycardia, induced by RyR2 gain-of-function mutation S2236L(±). We created a new biosensor to measure IMS-[Ca2+] in adult cardiomyocytes with intact Ca2+ cycling. We used ex vivo whole heart optical mapping, confocal and electron microscopy, as well as in vivo/in vitro gene editing techniques to test the effects of calpain in the IMS. We found altered mitochondrial cristae structure, increased IMS-[Ca2+], reduced OPA1 expression, and augmented mito-reactive oxygen species emission in catecholaminergic polymorphic ventricular tachycardia myocytes. We show that calpain-mediated OPA1 cleavage led to disrupted cristae organization and, thereby, decreased electron transport chain supercomplex assembly, resulting in accelerated reactive oxygen species production. Genetic inhibition of calpain activity in IMS reversed mitochondria structural defects in catecholaminergic polymorphic ventricular tachycardia myocytes and reduced arrhythmic burden in ex vivo optically mapped hearts. Our data suggest that RyR2 hyperactivity contributes to mitochondrial structural damage by promoting an increase in IMS-[Ca2+], sufficient to activate IMS-residing calpain. Calpain activation leads to proteolysis of OPA1 and cristae widening, thereby decreasing assembly of electron transport chain components into supercomplexes. Consequently, excessive mito-reactive oxygen species release critically contributes to RyR2 hyperactivation and ventricular tachyarrhythmia. Our new findings suggest that targeting IMS calpain may be beneficial in patients at risk for sudden cardiac death.

Presenilin mutations are the most common cause of familial Alzheimer's disease (FAD), but the mechanisms by which they disrupt neuronal function remain unresolved, particularly in relation to γ-secretase activity. Using Caenorhabditis elegans, we show that the presenilin ortholog SEL-12 supports synaptic transmission and axonal integrity through a pathway involving the ryanodine receptor RYR-1. Loss-of-function mutations in either sel-12 or ryr-1 reduce neurotransmitter release and cause neuronal structural defects, with no additional impairment in double mutants, suggesting a shared pathway. Transgenic expression of a γ-secretase-inactive SEL-12 variant or human presenilin 1 restores normal synaptic transmission in sel-12 mutants. Notably, sel-12 loss does not alter ryr-1 transcript or protein levels. These findings define a novel γ-secretase-independent role of presenilin in maintaining neuronal function via ryanodine receptor signaling, providing new mechanistic insight into presenilin-linked neurodegeneration and pointing to potential therapeutic strategies for FAD.

Disclosure: D.X. Ramos Padilla: None. R. Adupa: None. D. Suravajjala: None. A. Ammu: None. M. Rajput: None.Background: Dysglycemia is a known complication of fluoroquinolone use. However, severe hypoglycemia associated with ciprofloxacin use in a diabetic patient who is not on antidiabetic medications is rare and underreported. Ciprofloxacin has been linked to hypoglycemic episodes, but the mechanism and the risk in patients not on hypoglycemic therapy warrant further attention. Clinical Case: A 59-year-old man with a long history of Type 2 Diabetes Mellitus (T2DM), who had not been on any hypoglycemic therapy for over a year, experienced recurring episodes of severe hypoglycemia, culminating in a seizure. The patient had been taking oral and otic ciprofloxacin for a right ear infection for 7 days before the hypoglycemic episodes began. He was not on any antidiabetic medications, including insulin. Frequent episodes of shaking, clamminess, and sweating, accompanied by seizures, necessitated hospitalization. Documented blood glucose levels during the episodes were as low as 35 mg/dL. The hypoglycemic symptoms were reversed by administering dextrose and discontinuing ciprofloxacin. Discussion: Ciprofloxacin can block ATP-sensitive potassium channels (KATP) in pancreatic β-cells, leading to membrane depolarization, calcium influx, and increased insulin secretion. Additionally, it inhibits GLUT1, which reduces cellular glucose uptake, and induces calcium release from intracellular stores via ryanodine receptors, further promoting insulin secretion. These mechanisms collectively increase the risk of hypoglycemia in diabetic patients, even those not on antidiabetic medications, by boosting insulin secretion and disrupting glucose homeostasis. This case report underscores the potential for ciprofloxacin to induce severe hypoglycemia and neuroglycopenia in diabetic patients, even in the absence of antidiabetic medications. Although previous studies have noted the risk of hypoglycemia with fluoroquinolones, this report highlights the less recognized scenario of severe hypoglycemia associated with ciprofloxacin use in diabetic patients who are not on glucose-lowering treatments. Given the serious consequences of severe hypoglycemia, it is vital for clinicians to recognize this risk when prescribing ciprofloxacin, especially to diabetic patients. Clinicians should consider alternative antibiotics or ensure close blood glucose monitoring for diabetic patients on ciprofloxacin, regardless of their use of antidiabetic medications. By documenting and sharing such cases, the medical community can improve understanding of ciprofloxacin's risks and take appropriate steps to minimize them.Presentation: Saturday, July 12, 2025

ABSTRACTVentricular arrhythmias, a major cause of sudden cardiac death, are driven by Ca2+ imbalance in cardiac myocytes, often linked to the overactivation of CaMKIIδ (Ca2+/calmodulin‐dependent protein kinase II delta). As such, inhibiting CaMKIIδ represents a promising therapeutic strategy. Based on our previous finding that native secretoneurin (SN) is a weak CaMKIIδ inhibitor, we aimed to develop a more potent derivative of SN to effectively counter aberrant Ca2+ handling and arrhythmia risk. Various regions of SN were tested for CaMKII binding, identifying the core region as the sequence with the strongest binding capacity. This region was subsequently optimised with two phenylalanine substitutions, resulting in the SN derivative SN‐db‐short. Structural homology modeling and ELISA‐based assays revealed that SN‐db‐short bound both the substrate‐binding (S‐site) region of CaMKIIδ, in addition to the ATP‐binding region, with 8‐fold stronger binding compared to SN. Surface plasmon resonance experiments confirmed that SN‐db‐short exhibited a higher association rate and affinity for CaMKIIδ compared to SN. Consistent with only a partial calmodulin binding motif, SN‐db‐short showed no calmodulin binding, indicating selective CaMKIIδ inhibition. In functional studies, SN‐db‐short inhibited CaMKIIδ‐mediated phosphorylation of ryanodine receptor 2 and appeared more effective than SN in reducing the incidence of Ca2+ sparks and Ca2+ waves. SN‐db‐short also more markedly inhibited CaMKIIδ phosphorylation of phospholamban, slowed Ca2+ reuptake, and reduced the magnitude of Ca2+ transients during isoproterenol stimulation. SN‐db‐short effectively inhibits CaMKIIδ and significantly counters aberrant Ca2+ handling in cardiomyocytes. Thus, this optimised peptide holds therapeutic potential for reducing the risk of ventricular arrhythmias.

The ryanodine receptor isoform-1 (RyR1) is a large intracellular calcium release channel essential for skeletal muscle contraction. While cryo-electron microscopy has revealed structural snapshots of RyR1 in closed and open states, the dynamic features associated with calcium-dependent gating remain incompletely understood. In this study, we integrated all-atom molecular dynamics (MD) simulations with domain-level bioinformatics analyses to characterize and compare the structural dynamics of RyR1 in its closed and open conformations. Our simulations revealed distinct structural differences, including domain flexibility patterns, solvent accessibility, and hydrogen bonding networks, between the closed and open states. The closed state exhibited more extensive inter-subunit contacts and stable hydrogen-bonding networks, supporting a compact architecture characterized by inter-subunit domain engagement and intra-subunit domain loosening. In contrast, the open state showed increased solvent exposure and reduced inter-subunit interactions, reflecting inter-subunit domain loosening coupled with intra-subunit domain engagement, particularly in regions connecting the cytoplasmic and pore-forming domains. The comparative approach provides structural perspectives on how calcium binding may contribute to RyR1's conformational organization relevant to gating function. Our findings highlight the utility of integrating MD simulations with domain-scale analyses to investigate large protein complexes and generate hypotheses for future experimental validation.

Heart failure (HF) is a leading cause of mortality worldwide, characterized by structural and functional alterations that result in reduced cardiac function. During the progression of HF, cardiomyocytes undergo profound remodeling – including development of pathological hypertrophy and impaired calcium handling – which exacerbates cardiac dysfunction. Given the limited efficacy of current pharmacological treatments, there is an urgent need for novel mechanistically-orientated therapeutic strategies. Circular RNAs (circRNAs), a recently identified sub-class of non-coding RNAs, have emerged as pivotal regulators of diverse cellular processes in homeostasis and disease. We identified a significant repression of circRYR2 (mmu_circ_0000431), derived from the ryanodine receptor 2 (RYR2) locus, through global RNA profiling in hypertrophic compared to healthy murine hearts. Notably, a decreased expression of the human circRYR2 homologue hsa_circ_0112647 was also found in human failing hearts. Loss-of-function experiments in murine and human cardiomyocytes resulted in hypertrophic responses, whereas AAV-based overexpression of circRYR2 prevented cytokine-induced cardiomyocyte hypertrophy. Whole transcriptome analysis after circRYR2 depletion identified massive perturbations of calcium handling and contractility pathways. Indeed, modulation of circRYR2 affected the expression of the sarco/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a), and consequently, Ca2+ transients were assessed, revealing impaired or improved Ca2+ handling after circRYR2 knockdown or overexpression, respectively. In summary, the findings presented here provide new mechanistic insights for the circular RNA transcript derived from RYR2 locus and support circRYR2 overexpression strategies as promising therapeutic strategies for cardiac dysfunction.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05915-2.

ABSTRACTA novel RYR1 mutation (c.C5701T:p.Q1901X) was identified in a 51‐year‐old female presenting with acute respiratory failure as the primary manifestation of congenital myopathy. This case expands the genotype–phenotype spectrum of RYR1‐related myopathies and demonstrates that multidisciplinary intervention—including ventilator support, tracheostomy, and targeted rehabilitation—can significantly improve functional outcomes in late‐onset cases.

Alzheimer's disease (AD) is characterized by plaques and tangles, including calcium dysregulation and glycated products produced by reactive carbonyl compounds. AD brains have increased glyoxalase I (GLO1), a major scavenger of inflammatory carbonyl compounds, at early, but not later, stages of disease. Calcium dysregulation includes calcium leak from phosphorylated ryanodine receptor 2 (pS2808-RyR2), seen in aged macaques and AD mouse models, but the downstream consequences of calcium leak remain unclear. Here, we show that chronic calcium leak is associated with increased GLO1 expression and activity. In macaque, we found age-related increases in GLO1 expression in prefrontal cortex (PFC), correlating with pS2808-RyR2, and localized to dendrites and astrocytes. To examine the relationship between GLO1 and RyR2, we used S2808D-RyR2 mutant mice exhibiting chronic calcium leak through RyR2, and found increased GLO1 expression and activity in the PFC and hippocampus as early as 1-month and as late as 21-months of age, with a bell-shaped aging curve. These aged S2808D-RyR2 mice demonstrated impaired working memory. As with macaques, GLO1 was expressed in astrocytes and neurons. Proteomics data generated from S2808D-RyR2 synaptosomes confirmed GLO1 upregulation. Altogether, these data suggest potential association between GLO1 and chronic calcium leak, providing resilience in early stages of aging.

Histopathological and oxidative stress responses in the honey bee Apis mellifera larvae chronically exposed to environmentally relevant concentrations of cyantraniliprole.

Intracellular emetic signals involved in the cannabinoid CB1 receptor inverse agonist/antagonist SR141716A were investigated. SR141716A (20 mg/kg, i.p.)-evoked vomiting occurred via both the central and peripheral mechanisms. This was accompanied by robust emesis-associated increases in the following: (i) c-fos- and phospho-glycogen synthase kinase-3α/β (p-GSK-3αβ)-expression in the shrew’s dorsal vagal complex (DVC), (ii) phospho-extracellular signal-regulated kinase1/2 (p-ERK1/2) expression in both the DVC and jejunal enteric nervous system, and (iii) time-dependent upregulation of cAMP levels and phosphorylation of protein kinase A (PKA), protein kinase B (Akt), GSK-3α/β, ERK1/2, and protein kinase C αβII (PKCαβII) in the brainstem. SR141716A-evoked emetic parameters were attenuated by diverse inhibitors of the following: PKA, ERK1/2, GSK-3, phosphatidylinositol 3-kinase (PI3K)-Akt pathway, phospholipase C (PLC), PKC, Ca2+/calmodulin-dependent protein kinase II (CaMKII), L-type Ca2+ channel (LTCC), store-operated Ca2+ entry (SOCE), inositol trisphosphate receptor (IP3R), ryanodine receptor (RyRs), both 5-HT3-, and D2/3-receptor antagonists, and the transient receptor potential vanilloid 1 receptor (TRPV1R) agonist. SR141716A appears to evoke vomiting via inverse agonist activity involving emesis-associated kinases, including cAMP/PKA, ERK1/2, PI3K/Akt/GSK-3, PLC/PKCαβII, and CaMKII, which depend upon Ca2+ mobilization linking extracellular Ca2+ entry via plasma membrane Ca2+ channels (LTCC, SOCE, TRIPV1R) and intracellular Ca2+ release via IP3Rs and RyRs. The 5-HT3, NK1, and D2/3 receptors also contribute to SR141716A-mediated vomiting.