Molecular mechanisms of calcium-dependent excitotoxicity

2000 ◽  
Vol 78 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Rita Sattler ◽  
Michael Tymianski
Keyword(s):  
Molecular Mechanisms ◽  
Calcium Dependent

scholarly journals Genetic mapping and transcriptomic characterization of a new fuzzless-tufted cottonseed mutant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qian-Hao Zhu ◽  
Warwick Stiller ◽  
Philippe Moncuquet ◽  
Stuart Gordon ◽  
Yuman Yuan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Agronomic Traits ◽  
Gene Families ◽  
Mutant Phenotype ◽  
Wild Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Flanking Region ◽  
Comparative Transcriptomic Analysis

Abstract Fiber mutants are unique and valuable resources for understanding the genetic and molecular mechanisms controlling initiation and development of cotton fibers that are extremely elongated single epidermal cells protruding from the seed coat of cottonseeds. In this study, we reported a new fuzzless-tufted cotton mutant (Gossypium hirsutum) and showed that fuzzless-tufted near-isogenic lines (NILs) had similar agronomic traits and a higher ginning efficiency compared to their recurrent parents with normal fuzzy seeds. Genetic analysis revealed that the mutant phenotype is determined by a single incomplete dominant locus, designated N5. The mutation was fine mapped to an approximately 250-kb interval containing 33 annotated genes using a combination of bulked segregant sequencing, SNP chip genotyping, and fine mapping. Comparative transcriptomic analysis using 0–6 days post-anthesis (dpa) ovules from NILs segregating for the phenotypes of fuzzless-tufted (mutant) and normal fuzzy cottonseeds (wild-type) uncovered candidate genes responsible for the mutant phenotype. It also revealed that the flanking region of the N5 locus is enriched with differentially expressed genes (DEGs) between the mutant and wild-type. Several of those DEGs are members of the gene families with demonstrated roles in cell initiation and elongation, such as calcium-dependent protein kinase and expansin. The transcriptome landscape of the mutant was significantly reprogrammed in the 6 dpa ovules and, to a less extent, in the 0 dpa ovules, but not in the 2 and 4 dpa ovules. At both 0 and 6 dpa, the reprogrammed mutant transcriptome was mainly associated with cell wall modifications and transmembrane transportation, while transcription factor activity was significantly altered in the 6 dpa mutant ovules. These results imply a similar molecular basis for initiation of lint and fuzz fibers despite certain differences.

scholarly journals Axon degeneration: Molecular mechanisms of a self-destruction pathway

2012 ◽  
Vol 196 (1) ◽  
pp. 7-18 ◽  
Author(s):  
Jack T. Wang ◽  
Zachary A. Medress ◽  
Ben A. Barres
Keyword(s):  
Molecular Mechanisms ◽  
Nerve Degeneration ◽  
Axon Degeneration ◽  
Common Mechanism ◽  
Traumatic Injuries ◽  
Calcium Dependent ◽  
Survival Factor ◽  
Acute Injuries ◽  
Proposed Model ◽  
Axon Loss

Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown.

scholarly journals Initiating protease with modular domains interacts with β-glucan recognition protein to trigger innate immune response in insects

2015 ◽  
Vol 112 (45) ◽  
pp. 13856-13861 ◽  
Author(s):  
Daisuke Takahashi ◽  
Brandon L. Garcia ◽  
Michael R. Kanost
Keyword(s):  
Immune Responses ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Dependent Manner ◽  
Calcium Dependent ◽  
Amino Terminal ◽  
Density Lipoprotein Receptor ◽  
Recognition Protein

The autoactivation of an initiating serine protease upon binding of pattern recognition proteins to pathogen surfaces is a crucial step in eliciting insect immune responses such as the activation of Toll and prophenoloxidase pathways. However, the molecular mechanisms responsible for autoactivation of the initiating protease remains poorly understood. Here, we investigated the molecular basis for the autoactivation of hemolymph protease 14 (HP14), an initiating protease in hemolymph of Manduca sexta, upon the binding of β-1,3-glucan by its recognition protein, βGRP2. Biochemical analysis using HP14 zymogen (proHP14), βGRP2, and the recombinant proteins as truncated forms showed that the amino-terminal modular low-density lipoprotein receptor class A (LA) domains within HP14 are required for proHP14 autoactivation that is stimulated by its interaction with βGRP2. Consistent with this result, recombinant LA domains inhibit the activation of proHP14 and prophenoloxidase, likely by competing with the interaction between βGRP2 and LA domains within proHP14. Using surface plasmon resonance, we demonstrated that immobilized LA domains directly interact with βGRP2 in a calcium-dependent manner and that high-affinity interaction requires the C-terminal glucanase-like domain of βGRP2. Importantly, the affinity of LA domains for βGRP2 increases nearly 100-fold in the presence of β-1,3-glucan. Taken together, these results present the first experimental evidence to our knowledge that LA domains of an insect modular protease and glucanase-like domains of a βGRP mediate their interaction, and that this binding is essential for the protease autoactivation. Thus, our study provides important insight into the molecular basis underlying the initiation of protease cascade in insect immune responses.

scholarly journals MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Özgür Genç ◽  
Dion K Dickman ◽  
Wenpei Ma ◽  
Amy Tong ◽  
Richard D Fetter ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Calcium Influx ◽  
Homeostatic Plasticity ◽  
Calcium Sensor ◽  
C2 Domains ◽  
Calcium Dependent ◽  
Disease Associations ◽  
Transmembrane Regions ◽  
Presynaptic Calcium

Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from Drosophila to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified mctp (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal. Then, we demonstrate that MCTP functions downstream of presynaptic calcium influx with separable activities to stabilize baseline transmission, short-term release dynamics and PHP. Notably, PHP specifically requires the calcium coordinating residues in each of the three C2 domains of MCTP. Thus, we propose MCTP as a novel, ER-localized calcium sensor and a source of calcium-dependent feedback for the homeostatic stabilization of neurotransmission.

The MAP3K Apoptosis Signal-Regulating Kinase 1 (ASK1) Functions As a Calcium-Dependent Regulator of Platelet Activation Downstream of the G(α)q-PLC Signaling Axis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3720-3720
Author(s):  
Randall J. Derstine ◽  
Meghna U. Naik ◽  
Ulhas P. Naik
Keyword(s):  
Platelet Activation ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Conflicts Of Interest ◽  
Mapk Signaling ◽  
Human Platelets ◽  
Ros Scavenging ◽  
Calcium Dependent ◽  
Signaling Axis ◽  
Novel Target

Abstract Upon vascular injury, platelets rapidly adhere to sub-endothelial matrix proteins and activate to form a hemostatic platelet plug. Dysregulation of the molecular mechanisms dictating platelet plug formation is responsible for numerous thrombotic disorders. While it is known that MAPK signaling proteins such as p38, JNK, and ERK play a central role in platelet activation, little is known about the upstream MAP3K proteins regulating their activation following receptor stimulation. Our laboratory has identified the presence and activation of Apoptosis Signal-regulating Kinase 1 (ASK1), a member of the MAP3K family in human and mouse platelets. Ablation of Ask1 from mice results in a strong anti-thrombotic phenotype, and Ask1-/-platelets display significant functional defects such as integrin αIIbβ3 activation, granule secretion, and thromboxane A2 (TxA2) generation. To elucidate the signaling pathway leading to ASK1 activation, washed human platelets (4 x 108 platelets/mL) were evaluated for ASK1 phosphorylation at residue T845 (activated ASK1) by western blot analysis. Blocking TxA2 generation with aspirin (1 mM) severely diminished ASK1 activation induced by PAR1 peptide SFLLRN (100 μM), convulxin (10 ng/mL), and ADP (20 μM). Interestingly, PAR4 peptide AYPGKF (100 μM)-induced ASK1 activation was unaffected by aspirin treatment, suggesting AYPGKF-induced ASK1 activation to occur independently of TxA2 generation. The TxA2 mimetic, U46619, also induced strong T845 ASK1 phosphorylation. This data suggests ASK1 activation in human platelets to occur downstream of the TxA2 receptor TP-α and thrombin receptor PAR4. In nucleated cells, ASK1 is primarily activated by reactive oxygen species (ROS) following oxidative stress. The mechanism of ASK1 activation in platelets has never been studied. Treatment of washed human platelets (4 x 108 platelets/mL) with the ROS donor hydrogen peroxide (1 μM) failed to induce ASK1 activation. Additionally, scavenging of intracellular ROS by the ROS-scavenging compound MnTMPyP (200 μM) had no effect on agonist-induced ASK1 activation suggesting that ASK1 is activated by a ROS-independent mechanism. Interestingly, inducing intracellular calcium rise with the SERCA inhibitor, thapsigargin (1 µM), resulted in strong activation of ASK1 in human platelets. Blocking calcium rise using the calcium chelator BAPTA (50 μM) blocked both thapsigargin and agonist-induced ASK1 activation. This apparent dependency on calcium for ASK1 activation was also observed in the megakaryoblastic cell line MEG-01. Inhibition of IP3-mediated calcium release using the PLC inhibitor U73122 (10 μM) was sufficient to block ASK1 activation induced by U46619 (5 μM) and AYPGKF (100 μM), providing further evidence of a calcium-dependent mechanism for ASK1 activation in human platelets. The identification of ASK1 in platelets and the observed defects in Ask1-/-murine platelets as well as the impaired thrombosis highlights the central role of ASK1 in mediating platelet activation which, until this point, has largely been overlooked. In addition, the observation that ASK1 activation in platelets is exclusively calcium-dependent makes platelets to be a unique model for studying calcium-dependent ASK1 signaling that is independent of ROS. Collectively, we strongly believe that ASK1 is a novel target for anti-thrombotic drug therapy. Disclosures No relevant conflicts of interest to declare.

Characterization of Arabidopsis calcium-dependent protein kinases: activated or not by calcium?

2012 ◽  
Vol 447 (2) ◽  
pp. 291-299 ◽  
Author(s):  
Marie Boudsocq ◽  
Marie-Jo Droillard ◽  
Leslie Regad ◽  
Christiane Laurière
Keyword(s):  
Protein Kinases ◽  
Calcium Binding ◽  
Molecular Mechanisms ◽  
Calcium Sensitivity ◽  
In Planta ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Biochemical Level ◽  
Calcium Dependent Protein Kinases ◽  
Ef Hands

CDPKs (calcium-dependent protein kinases), which contain both calmodulin-like calcium binding and serine/threonine protein kinase domains, are only present in plants and some protozoans. Upon activation by a stimulus, they transduce the signal through phosphorylation cascades to induce downstream responses, including transcriptional regulation. To understand the functional specificities of CDPKs, 14 Arabidopsis CPKs (CDPKs in plants) representative of the three main subgroups were characterized at the biochemical level, using HA (haemagglutinin)-tagged CPKs expressed in planta. Most of them were partially or mainly associated with membranes, in agreement with acylation predictions. Importantly, CPKs displayed highly variable calcium-dependences for their kinase activities: seven CPKs from subgroups 1 and 2 were clearly sensitive to calcium with different intensities, whereas six CPKs from subgroup 3 exhibited low or no calcium sensitivity to two generic substrates. Interestingly, this apparent calcium-independence correlated with significant alterations in the predicted EF-hands of these kinases, although they all bound calcium. The noticeable exception, CPK25, was calcium-independent owing to the absence of functional EF-hands. Taken together, the results of the present study suggest that calcium binding differentially affects CDPK isoforms that may be activated by distinct molecular mechanisms.

Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity

Cell Calcium ◽  
2003 ◽  
Vol 34 (4-5) ◽  
pp. 325-337 ◽  
Author(s):  
Mark Arundine ◽  
Michael Tymianski
Keyword(s):  
Molecular Mechanisms ◽  
Calcium Dependent

Role of the Wnt signalling pathway in the development of endothelial disorders in response to hyperglycaemia

2019 ◽  
Vol 21 ◽  
Author(s):  
Martyna Durak-Kozica ◽  
Elżbieta Paszek ◽  
Ewa Ł Stępień
Keyword(s):  
Planar Cell Polarity ◽  
Wnt Pathway ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Control Cell ◽  
Vascular Complications ◽  
Calcium Dependent ◽  
Expression Of Genes ◽  
Life Threatening ◽  
Dependent Pathway

Abstract Introduction Diabetes mellitus (DM) is the most common metabolic disease. A WHO report from 2016 indicates that 422 million people worldwide suffer from DM or hyperglycaemia because of impaired glucose metabolism. Chronic hyperglycaemia leads to micro- and macrovessel damage, which may result in life-threatening complications. The Wnt pathway regulates cell proliferation and survival by modulating the expression of genes that control cell differentiation. Three linked Wnt pathways have been discovered thus far: a β-catenin-dependent pathway and two pathways independent of β-catenin – the planar cell polarity pathway and calcium-dependent pathway. The Wnt pathway regulates genes associated with inflammation, cell cycle, angiogenesis, fibrinolysis and other molecular processes. Areas covered This review presents the current state of knowledge regarding the contribution of the Wnt pathway to endothelial ageing under hyperglycaemic conditions and provides new insights into the molecular basis of diabetic endothelial dysfunction. Conclusion The β-catenin-dependent pathway is a potential target in the prophylaxis and treatment of early-stage diabetes-related vascular complications. However, the underlying molecular mechanisms remain largely undetermined and require further investigation.

scholarly journals Calcium-dependent properties of CIB binding to the integrin αIIb cytoplasmic domain and translocation to the platelet cytoskeleton

1999 ◽  
Vol 342 (3) ◽  
pp. 729-735 ◽  
Author(s):  
David D. SHOCK ◽  
Ulhas P. NAIK ◽  
Julia E. BRITTAIN ◽  
Suresh K. ALAHARI ◽  
John SONDEK ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Cytoplasmic Domain ◽  
Titration Calorimetry ◽  
Dependent Manner ◽  
Calcium Dependent ◽  
Fibrinogen Binding ◽  
Ef Hand ◽  
Domain Peptide ◽  
Triton X

The αIIbβ3 integrin receives signals in agonist-activated platelets, resulting in its conversion to an active conformation that binds fibrinogen, thereby mediating platelet aggregation. Fibrinogen binding to αIIbβ3 subsequently induces a cascade of intracellular signalling events. The molecular mechanisms of this bi-directional αIIbβ3-mediated signalling are unknown but may involve the binding of proteins to the integrin cytoplasmic domains. We reported previously the sequence of a novel 22-kDa, EF-hand-containing, protein termed CIB (calcium- and integrin-binding protein) that interacts specifically with the αIIb cytoplasmic domain in the yeast two-hybrid system. Further analysis of numerous tissues and cell lines indicated that CIB mRNA and protein are widely expressed. In addition, isothermal titration calorimetry indicated that CIB binds to an αIIb cytoplasmic-domain peptide in a Ca2+-dependent manner, with moderate affinity (Kd, 700 nM) and 1:1 stoichiometry. In aggregated platelets, endogenous CIB and αIIbβ3 translocate to the Triton X-100-insoluble cytoskeleton in a parallel manner, demonstrating that the cellular localization of CIB is regulated, potentially by αIIbβ3. Thus CIB may contribute to integrin-related functions by mechanisms involving Ca2+-modulated binding to the αIIb cytoplasmic domain and changes in intracellular distribution.

scholarly journals Transcriptional regulation of IL-6 in bile duct epithelia by extracellular ATP

2009 ◽  
Vol 296 (3) ◽  
pp. G563-G571 ◽  
Author(s):  
Jin Yu ◽  
Nina Sheung ◽  
Elwy M. Soliman ◽  
Carlo Spirli ◽  
Jonathan A. Dranoff
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Molecular Mechanisms ◽  
Cytosolic Calcium ◽  
Extracellular Atp ◽  
Site Directed Mutagenesis ◽  
Extracellular Nucleotides ◽  
Calcium Dependent ◽  
Calcium Agonists ◽  
Process Effects

The inflammatory cytokine IL-6 is essential for cell survival after liver injury. Bile duct epithelia (BDE) markedly upregulate IL-6 release after liver injury, but the mechanisms regulating this have not been defined. Purinergic signals induce multiple potent downstream effects in BDE, so the goals of this study were to determine whether extracellular ATP regulates BDE IL-6 transcription and to identify the molecular mechanisms regulating this process. Effects of extracellular nucleotides on IL-6 transcription in primary rat bile duct epithelia were assessed. The relative effects of cAMP and cytosolic calcium were determined by use of agonists and antagonists. The role of the cAMP response element (CRE) was determined by site-directed mutagenesis. We found that ATP potently upregulated IL-6 mRNA, and that the pharmacological profile for IL-6 upregulation was most consistent with the newly identified P2Y11 receptor. This occurred in a cAMP-dependent and calcium-dependent fashion. The effect of cAMP and calcium agonists on IL-6 promoter activity was synergistic, and mutation of the IL-6 CRE blocked upregulation by ATP. Taken together, these data show that extracellular ATP acts through a mechanism involving a rat P2Y receptor functionally related to the P2Y11 receptor, cAMP, and calcium signals and that the IL-6 promoter CRE to upregulate transcription of IL-6 in BDE. Since IL-6 has such critical importance in the liver, it is likely that this pathway is of great relevance to the understanding of hepatic response to injury.

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