scholarly journals Ca2+/CaM binding to CaMKI promotes IMA-3 importin binding and nuclear translocation in sensory neurons to control behavioral adaptation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Domenica Ippolito ◽  
Saurabh Thapliyal ◽  
Dominique A Glauser
Keyword(s):  
Cell Activation ◽  
Behavioral Plasticity ◽  
Nuclear Translocation ◽  
Neural Activation ◽  
Sensory Adaptation ◽  
Transcription Control ◽  
C Elegans ◽  
Regulatory Processes ◽  
Slow Kinetics

Sensory and behavioral plasticity are essential for animals to thrive in changing environments. As key effectors of intracellular calcium signaling, Ca2+/Calmodulin-dependent protein kinases (CaMKs) can bridge neural activation with the many regulatory processes needed to orchestrate sensory adaptation, including by relaying signals to the nucleus. Here, we elucidate the molecular mechanism controlling the cell activation-dependent nuclear translocation of CMK-1, the C. elegans ortholog of mammalian CaMKI/IV, in thermosensory neurons in vivo. We show that an intracellular Ca2+ concentration elevation is necessary and sufficient to favor CMK-1 nuclear import. The binding of Ca2+/CaM to CMK-1 increases its affinity for IMA-3 importin, causing a redistribution with a relatively slow kinetics, matching the timescale of sensory adaptation. Furthermore, we show that this mechanism enables the encoding of opposite nuclear signals in neuron types with opposite calcium-responses and that it is essential for experience-dependent behavioral plasticity and gene transcription control in vivo. Since CaMKI/IV are conserved regulators of adaptable behaviors, similar mechanisms could exist in other organisms and for other sensory modalities.

scholarly journals Mitochondrial Ca2+ Dynamics in MCU Knockout C. elegans Worms

2020 ◽  
Vol 21 (22) ◽  
pp. 8622
Author(s):  
Pilar Álvarez-Illera ◽  
Paloma García-Casas ◽  
Rosalba I Fonteriz ◽  
Mayte Montero ◽  
Javier Alvarez
Keyword(s):  
Cell Activation ◽  
Physiological Activity ◽  
Large Cell ◽  
Atp Production ◽  
Physiological Conditions ◽  
C Elegans ◽  
Neuronal Stimulation ◽  
Low Amplitude ◽  
Stimulation Of

Mitochondrial [Ca2+] plays an important role in the regulation of mitochondrial function, controlling ATP production and apoptosis triggered by mitochondrial Ca2+ overload. This regulation depends on Ca2+ entry into the mitochondria during cell activation processes, which is thought to occur through the mitochondrial Ca2+ uniporter (MCU). Here, we have studied the mitochondrial Ca2+ dynamics in control and MCU-defective C. elegans worms in vivo, by using worms expressing mitochondrially-targeted YC3.60 yellow cameleon in pharynx muscle. Our data show that the small mitochondrial Ca2+ oscillations that occur during normal physiological activity of the pharynx were very similar in both control and MCU-defective worms, except for some kinetic differences that could mostly be explained by changes in neuronal stimulation of the pharynx. However, direct pharynx muscle stimulation with carbachol triggered a large and prolonged increase in mitochondrial [Ca2+] that was much larger in control worms than in MCU-defective worms. This suggests that MCU is necessary for the fast mitochondrial Ca2+ uptake induced by large cell stimulations. However, low-amplitude mitochondrial Ca2+ oscillations occurring under more physiological conditions are independent of the MCU and use a different Ca2+ pathway.

scholarly journals Identification of phenolic secondary metabolites from Schotia brachypetala Sond. (Fabaceae) and demonstration of their antioxidant activities in Caenorhabditis elegans

2016 ◽  
Author(s):  
Mansour Sobeh ◽  
Esraa A ElHawary ◽  
Herbenya Peixoto ◽  
Rola M Labib ◽  
Heba Handoussa ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Caenorhabditis Elegans ◽  
Nuclear Translocation ◽  
Antioxidant Activities ◽  
In Vitro Assays ◽  
Flavonoid Glycosides ◽  
Alcoholic Extract ◽  
C Elegans

Background: Schotia brachypetala Sond. (Fabaceae) is an endemic tree of Southern Africa whose phytochemistry and pharmacology were slightly studied.The present work aimed at profiling the major phenolics compounds present in the hydro-alcoholic extract from S. brachypetala leaves (SBE) using LC/HRESI/MS/MS and NMR and prove their antioxidant capabilities using novel methods. Methods: In vitro assays; DPPH, TEAC persulfate decolorizing kinetic and FRAP assays, and in vivo assays: Caenorhabditis elegans strains maintenance, Intracellular ROS in C. elegans, Survival assay, GFP expression and Subcellular DAF-16 localization were employed to evaluate the antioxidant activity. Results: More than forty polyphenols ,including flavonoid glycosides, galloylated flavonoid glycosides, isoflavones, dihydrochalcones, procyanidins, anthocyanins, hydroxybenzoic acid derivatives, hydrolysable tannins, and traces of methylated and acetylated flavonoid derivatives were identified. Three compounds were isolated and identified from the genus Schotia for the first time, namely gallic acid, myricetin-3-O-α-L-1C4-rhamnoside and quercetin-3-O-L-1C4-rhamnoside.The tested extract was able to protect the worms against juglone induced oxidative stress and attenuate the reactive oxygen species (ROS) accumulation. SBE was also able to attenuate the levels of heat shock protein (HSP) expression. Discussion: A pronounced antioxidant activity in vivo, which can be attributed to its ability to promote the nuclear translocation of DAF-16/FOXO, the main transcription factor regulating the expression of stress response genes. The remarkable antioxidant activity in vitro and in vivo correlates to SBE rich phenolic profile.

Prevention of NF-κB activation in vivo by a cell-permeable NF-κB inhibitor peptide

2005 ◽  
Vol 289 (4) ◽  
pp. L536-L544 ◽  
Author(s):  
Ana L. Mora ◽  
John LaVoy ◽  
Martha McKean ◽  
Arlene Stecenko ◽  
Kenneth L. Brigham ◽  
...  
Keyword(s):  
Recombinant Protein ◽  
Stress Responses ◽  
Cell Activation ◽  
Immune Cell ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
New Approach ◽  
Immune Cell Activation ◽  
A Cell

The NF-κB/Rel transcription factor family plays a central role in coordinating the expression of a variety of genes that regulate stress responses, immune cell activation, apoptosis, proliferation, differentiation, and oncogenic transformation. Interventions that target the NF-κB pathway may be therapeutic for a variety of pathologies, especially immune/inflammatory diseases. Using membrane translocating sequence (MTS) technology, we developed a cell-permeable dominant inhibitor of NF-κB activation, termed IκBα-(ΔN)-MTS. This molecule contains a 12-amino acid MTS motif attached to the COOH-terminal region of a nondegradable inhibitor protein [IκBα-(ΔN)]. The recombinant protein enters cells and localizes in the cytoplasm. Delivery of the IκBα-(ΔN)-MTS to cell lines and primary cells inhibited nuclear translocation of NF-κB proteins induced by cell activation. The protein also effectively inhibited NF-κB activation in vivo in two different animal models: NF-κB activation in response to skin wounding in mice and NF-κB activation in lungs after endotoxin treatment in sheep. Inhibition of NF-κB by the IκBα-(ΔN)-MTS in the endotoxin model attenuated physiological responses to endotoxemia. These data demonstrate that activation of NF-κB can be inhibited using a recombinant protein designed to penetrate into cells. This technology may provide a new approach to NF-κB pathway-targeted therapies.

scholarly journals Identification of phenolic secondary metabolites from Schotia brachypetala Sond. (Fabaceae) and demonstration of their antioxidant activities in Caenorhabditis elegans

2016 ◽  
Author(s):  
Mansour Sobeh ◽  
Esraa A ElHawary ◽  
Herbenya Peixoto ◽  
Rola M Labib ◽  
Heba Handoussa ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Caenorhabditis Elegans ◽  
Nuclear Translocation ◽  
Antioxidant Activities ◽  
In Vitro Assays ◽  
Flavonoid Glycosides ◽  
Alcoholic Extract ◽  
C Elegans

Background: Schotia brachypetala Sond. (Fabaceae) is an endemic tree of Southern Africa whose phytochemistry and pharmacology were slightly studied.The present work aimed at profiling the major phenolics compounds present in the hydro-alcoholic extract from S. brachypetala leaves (SBE) using LC/HRESI/MS/MS and NMR and prove their antioxidant capabilities using novel methods. Methods: In vitro assays; DPPH, TEAC persulfate decolorizing kinetic and FRAP assays, and in vivo assays: Caenorhabditis elegans strains maintenance, Intracellular ROS in C. elegans, Survival assay, GFP expression and Subcellular DAF-16 localization were employed to evaluate the antioxidant activity. Results: More than forty polyphenols ,including flavonoid glycosides, galloylated flavonoid glycosides, isoflavones, dihydrochalcones, procyanidins, anthocyanins, hydroxybenzoic acid derivatives, hydrolysable tannins, and traces of methylated and acetylated flavonoid derivatives were identified. Three compounds were isolated and identified from the genus Schotia for the first time, namely gallic acid, myricetin-3-O-α-L-1C4-rhamnoside and quercetin-3-O-L-1C4-rhamnoside.The tested extract was able to protect the worms against juglone induced oxidative stress and attenuate the reactive oxygen species (ROS) accumulation. SBE was also able to attenuate the levels of heat shock protein (HSP) expression. Discussion: A pronounced antioxidant activity in vivo, which can be attributed to its ability to promote the nuclear translocation of DAF-16/FOXO, the main transcription factor regulating the expression of stress response genes. The remarkable antioxidant activity in vitro and in vivo correlates to SBE rich phenolic profile.

Naturally occurring short splice variant of CYLD positively regulates dendritic cell function

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5891-5895 ◽  
Author(s):  
Cathy Cecilia Srokowski ◽  
Joumana Masri ◽  
Nadine Hövelmeyer ◽  
Anna Katharina Krembel ◽  
Christine Tertilt ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Splice Variant ◽  
Cell Activation ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Naturally Occurring ◽  
Short Splice Variant

Abstract Deubiquitination of NF-κB members by CYLD is crucial in controlling the magnitude and nature of cell activation. The role of the naturally occurring CYLD splice variant in dendritic cell (DC) function was analyzed using CYLDex7/8 mice, which lack the full-length CYLD (flCYLD) transcript and overexpress the short splice variant (sCYLD). Bone marrow–derived DCs from CYLDex7/8 mice display a hyperactive phenotype in vitro and in vivo and have a defect in establishing tolerance with the use of DEC-205–mediated antigen targeting to resting DCs. The combination of sCYLD overexpression and lack of flCYLD in CYLDex7/8 DCs leads to enhanced NF-κB activity accompanied by an increased nuclear translocation of the IκB molecule Bcl-3, along with nuclear p50 and p65. This suggests that, in contrast to flCYLD, sCYLD is a positive regulator of NF-κB activity, and its overexpression induces a hyperactive phenotype in DCs.

scholarly journals Integration of plasticity mechanisms within a single sensory neuron of C. elegans actuates a memory

2017 ◽  
Author(s):  
Josh D. Hawk ◽  
Ana C. Calvo ◽  
Agustin Almoril-Porras ◽  
Ahmad Aljobeh ◽  
Maria Luisa Torruella-Suárez ◽  
...  
Keyword(s):  
Single Cell ◽  
Sensory Neuron ◽  
Neural Plasticity ◽  
Sensory Information ◽  
Sensory Adaptation ◽  
Sensory Stimuli ◽  
C Elegans ◽  
Presynaptic Plasticity ◽  
Behavioral Preference

SummaryNeural plasticity—the ability of a neuron to change its cellular properties in response to past experiences—underpins the nervous system’s capacity to form memories and actuate behaviors. How different plasticity mechanisms act together in vivo and at a cellular level to transform sensory information into behavior is not well understood. Here we show that in the nematode C. elegans two plasticity mechanisms—sensory adaptation and presynaptic plasticity—act within a single cell to encode thermosensory information and actuate a temperature-preference memory. Sensory adaptation enables the primary thermosensory neuron, AFD, to adjust the temperature range of its sensitivity to the local environment, thereby optimizing its ability to detect temperature fluctuations associated with migration. Presynaptic plasticity transforms this thermosensory information into a behavioral preference by gating synaptic communication between sensory neuron AFD and its postsynaptic partner, AIY. The gating of synaptic communication is regulated at AFD presynaptic sites by the conserved kinase nPKCε. Bypassing or altering AFD presynaptic plasticity predictably changes the learned behavioral preferences without affecting sensory responses. Our findings indicate that two distinct and modular neuroplasticity mechanisms function together within a single sensory neuron to encode multiple components of information required to enact thermotactic behavior. The integration of these plasticity mechanisms result in a single-cell logic system that can both represent sensory stimuli and guide memory-based behavioral preference.

scholarly journals Safranal Alleviated OVA-Induced Asthma Model and Inhibits Mast Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Peeraphong Lertnimitphun ◽  
Wenhui Zhang ◽  
Wenwei Fu ◽  
Baican Yang ◽  
Changwu Zheng ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Inhibitory Effect ◽  
Crocus Sativus ◽  
Mast Cell Activation ◽  
Asthma Model ◽  
Tnf Α

IntroductionAsthma is a chronic and recurring airway disease, which related to mast cell activation. Many compounds derived from Chinese herbal medicine has promising effects on stabilizing mast cells and decreasing inflammatory mediator production. Safranal, one of the active compounds from Crocus sativus, shows many anti-inflammatory properties. In this study, we evaluated the effect of safranal in ovalbumin (OVA)-induced asthma model. Furthermore, we investigate the effectiveness of safranal on stabilizing mast cell and inhibiting the production of inflammatory mediators in passive systemic anaphylaxis (PSA) model.MethodsOVA-induced asthma and PSA model were used to evaluate the effect of safranal in vivo. Lung tissues were collected for H&E, TB, IHC, and PAS staining. ELISA were used to determine level of IgE and chemokines (IL-4, IL-5, TNF-α, and IFN-γ). RNA sequencing was used to uncovers genes that safranal regulate. Bone marrow-derived mast cells (BMMCs) were used to investigate the inhibitory effect and mechanism of safranal. Cytokine production (IL-6, TNF-α, and LTC4) and NF-κB and MAPKs signaling pathway were assessed.ResultsSafranal reduced the level of serum IgE, the number of mast cells in lung tissue were decreased and Th1/Th2 cytokine levels were normalized in OVA-induced asthma model. Furthermore, safranal inhibited BMMCs degranulation and inhibited the production of LTC4, IL-6, and TNF-α. Safranal inhibits NF-κB and MAPKs pathway protein phosphorylation and decreases NF-κB p65, AP-1 nuclear translocation. In the PSA model, safranal reduced the levels of histamine and LTC4 in serum.ConclusionsSafranal alleviates OVA-induced asthma, inhibits mast cell activation and PSA reaction. The possible mechanism occurs through the inhibition of the MAPKs and NF-κB pathways.

Caenorhabditis elegans lin-25: A Study of Its Role in Multiple Cell Fate Specification Events Involving Ras and the Identification and Characterization of Evolutionarily Conserved Domains

Genetics ◽  
2000 ◽  
Vol 156 (3) ◽  
pp. 1083-1096
Author(s):  
Lars Nilsson ◽  
Teresa Tiensuu ◽  
Simon Tuck
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Nuclear Translocation ◽  
Cell Fate Specification ◽  
Sequence Comparisons ◽  
Vulval Development ◽  
Fate Specification ◽  
C Elegans

Abstract Caenorhabditis elegans lin-25 functions downstream of let-60 ras in the genetic pathway for the induction of the 1° cell fate during vulval development and encodes a novel 130-kD protein. The biochemical activity of LIN-25 is presently unknown, but the protein appears to function together with SUR-2, whose human homologue binds to Mediator, a protein complex required for transcriptional regulation. We describe here experiments that indicate that, besides its role in vulval development, lin-25 also participates in the fate specification of a number of other cells in the worm that are known to require Ras-mediated signaling. We also describe the cloning of a lin-25 orthologue from C. briggsae. Sequence comparisons suggest that the gene is evolving relatively rapidly. By characterizing the molecular lesions associated with 10 lin-25 mutant alleles and by assaying in vivo the activity of mutants lin-25 generated in vitro, we have identified three domains within LIN-25 that are required for activity or stability. We have also identified a sequence that is required for efficient nuclear translocation. We discuss how lin-25 might act in cell fate specification in C. elegans within the context of models for lin-25 function in cell identity and cell signaling.

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