Regulation of brain-specific kinases 1 and 2 (BRSK1/2) by Ca2+/calmodulin.

The impact of lactate on diabetic cognitive dysfunction: Insights from energy metabolism to epigenetic modulation.

Calcium plays a crucial role as a second messenger in neuronal signal transduction pathways. The influx of calcium ions through various physicochemical gating channels activates neuronal calcium signaling. The Endoplasmic Reticulum (ER) is a significant intracellular structure that sequesters calcium and controls signaling through SERCA, IPR, and leak channel mechanisms. Disruption of calcium dynamics can trigger intrinsic dyshomeostasis, cell damage, and apoptosis. The present study articulates a Caputo fractional time derivative in the polar coordinate dimensions to investigate the role of nonlocal calcium-free ions in the neuron through the Orai channel, and ER fluxes, incorporating various physiological parameters. The solution was obtained through the hybrid integral transform technique for analytical form. The closed form was generated using Green's function in terms of Mainardi and Wright's functions. Our simulation uncovered the calcium concentration bandwidth of interaction with different neuronal parameters. Parameters and calcium ion synergy show normal and Alzheimer's disease-impacted interaction through different illustrations. Our simulation reveals that S100B and BAPTA have significant calcium-controlling behavior.

Bipolar disorder (BD) is a complex and serious psychiatric condition primarily characterized by bipolar depression, with the underlying genetic determinants yet to be elucidated. There is a substantial body of literature linking psychiatric disorders, including BD, to oxidative stress (OS). Consequently, this study aims to assess the relationship between BD and OS by identifying key hub genes implicated in OS pathways. We acquired gene microarray data from GSE5392 through the Gene Expression Omnibus (GEO). Our approach encompassed differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Protein-Protein Interaction (PPI) Network analysis to pinpoint hub genes associated with BD. Subsequently, we utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) to identify hub genes relevant to OS. To evaluate the diagnostic accuracy of these hub genes, we performed receiver operating characteristic curve (ROC) analysis on both GSE5388 and GSE5389 datasets. Furthermore, we conducted a study involving ten BD patients and ten healthy controls (HCs) who met the special criteria, assessing the expression levels of these hub genes in their peripheral blood mononuclear cells (PBMCs). We identified 411 down-regulated genes and 69 up-regulated genes for further scrutiny. Through WGCNA, we obtained 22 co-expression modules, with the sienna3 module displaying the strongest association with BD. By integrating differential analysis with genes linked to OS, we identified 44 common genes. Subsequent PPI Network and WGCNA analyses confirmed three hub genes as potential biomarkers for BD. Functional enrichment pathway analysis revealed their involvement in neuronal signal transduction, oxidative phosphorylation, and metabolic obstacle pathways. Using the Cytoscape plugin "ClueGo assay," we determined that a majority of these targets regulate neuronal synaptic plasticity. ROC curve analysis underscored the excellent diagnostic value of these three hub genes. Quantitative reverse transcription-PCR (RT-qPCR) results indicated significant changes in the expression of these hub genes in the PBMCs of BD patients compared to HCs. We identified three hub genes (TAC1, MAP2K1, and MAP2K4) in BD associated with OS, potentially influencing the diagnosis and treatment of BD. Based on the GEO database, our study provides novel insights into the relationship between BD and OS, offering promising therapeutic targets.

Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks

Long-term synaptic plasticity is shaped by the controlled reorganization of the synaptic proteome. A key component of this process is local proteolysis performed by the family of extracellular matrix metalloproteinases (MMPs). In recent years, considerable progress was achieved in identifying extracellular proteases involved in neuroplasticity phenomena and their protein substrates. Perisynaptic metalloproteinases regulate plastic changes at synapses through the processing of extracellular and membrane proteins. MMP9 was found to play a crucial role in excitatory synapses by controlling the NMDA-dependent LTP component. In addition, MMP3 regulates the L-type calcium channel-dependent form of LTP as well as the plasticity of neuronal excitability. Both MMP9 and MMP3 were implicated in memory and learning. Moreover, altered expression or mutations of different MMPs are associated with learning deficits and psychiatric disorders, including schizophrenia, addiction, or stress response. Contrary to excitatory drive, the investigation into the role of extracellular proteolysis in inhibitory synapses is only just beginning. Herein, we review the principal mechanisms of MMP involvement in the plasticity of excitatory transmission and the recently discovered role of proteolysis in inhibitory synapses. We discuss how different matrix metalloproteinases shape dynamics and turnover of synaptic adhesome and signal transduction pathways in neurons. Finally, we discuss future challenges in exploring synapse- and plasticity-specific functions of different metalloproteinases.

Intracranial self-stimulation-reward or immobilization-aversion had different effects on neurite extension and the ERK pathway in neurotransmitter-sensitive mutant PC12 cells

Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons.

Serine/Threonine protein phosphatases regulate the activity of insulin signaling molecules involved in glucose homeostasis. Aberration in their functions have been reported in adipocytes, hepatocytes and skeletal muscle cells lead to abnormalities in signal transduction causing diabetes. Neuronal system is insulin responsive. Malfunctions have been reported to lead to development of metabolic disorders like diabetic neuropathy and Alzheimer disease. Our understanding of phosphatase mediated regulation in general is anyway very limited and role of PP2C in insulin signaling pathway in neuronal system is practically non-existent. Further exploration is required to understand the role of Ser/Thr phosphatases in neuronal system. Therefore, the aim of this work was to identify the role of PP2C in neuronal insulin signaling. To achieve this, PP2C in the differentiated Neuro-2a (N2A) cells was inhibited by treating with a potent and specific inhibitor of PP2C, Sanguinarine Chloride (SC), in presence (100nM) or absence of insulin and the effect was tested on the activity of AS160 and GSK3β. In insulin stimulated state inhibition of PP2C caused a significant 37% and 56% of decrease in the phosphorylation of AS160 at Ser588 and Thr642 residues, respectively. Similarly, a 37% decrease was observed in phosphorylation of GSK3β at Ser9. However, the expression of AS160 and GSK3β were found to be unaffected. Data shows for the first time that PP2C mediated dephosphorylation might be involved in regulating the activity of AS160 and GSK3β in neuronal system and hence suggest a possibility of its playing a major negative role in regulating neuronal insulin signal transduction pathway. Disclosure Y. Yadav: None. C.S. Dey: None. Funding Department of Science & Technology, Government of India, New Delhi; Department of Science & Technology, Government of India, New Delhi (SR/S2/JCB-24/2008(G))

Dementia and diabetes mellitus are prevalent disorders in the elderly population. While recognized as two distinct diseases, diabetes has more recently recognized as a significant contributor to risk for developing dementia, and some studies make reference to type 3 diabetes, a condition resulting from insulin resistance in the brain. Alzheimer's disease, the most common form of dementia, and diabetes, interestingly, share underlying pathological processes, commonality in risk factors, and, importantly, pathways for intervention. Tea has been suggested to possess potent antioxidant properties. It is rich in phytochemicals including, flavonoids, tannins, caffeine, polyphenols, boheic acid, theophylline, theobromine, anthocyanins, gallic acid, and finally epigallocatechin-3-gallate, which is considered to be the most potent active ingredient. Flavonoid phytochemicals, known as catechins, within tea offer potential benefits for reducing the risk of diabetes and Alzheimer's disease by targeting common risk factors, including obesity, hyperlipidemia, hypertension, cardiovascular disease, and stroke. Studies also show that catechins may prevent the formation of amyloid-β plaques and enhance cognitive functions, and thus may be useful in treating patients who have Alzheimer's disease or dementia. Furthermore, other phytochemicals found within tea offer important antioxidant properties along with innate properties capable of modulating intracellular neuronal signal transduction pathways and mitochondrial function.

ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion

Potassium (K+) channels constitute the most diverse class of ion channels; these channels are especially important for regulation of the neuronal excitability and provide signaling activity in a variety of ways. These channels are major determinants of the membrane excitability, influencing the resting potential of the membranes, waveforms and frequencies of action potentials, and thresholds of excitation. Voltagegated K+ channels do not exist as independent units merely responding to changes in the transmembrane potential; these are macromolecular complexes able to integrate a great variety of cellular signals that provide fine tuning of channel activities. Compounds that change K+ channel properties are commonly employed as therapeutic agents in a number of pathologies, in particular arrhythmias, cancer, and neurological disorders (psychoses, epilepsy, stroke, and Alzheimer’s disease).

Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell-cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen-glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance.

To study the effect of ginsenoside Rb1 on GSKbeta/IDE signal transduction pathway and Abeta protein secretion in hippocampal neurons of high glucose-treated rats. Hippocampal neurons of 24 h-old newly born SD rats were primarily cultured, inoculated in culture medium under different conditions, and then divided into the normal group, the high glucose group, the LiCl group and the Rb1 group. After being cultured for 72 h, the expressions of their phosphorylated GSK3beta, total GSK3beta and IDE protein were detected by Western blotting analysis. The mRNA expressions of GSK3beta and IDE were determined by RT-PCR. The ELISA assay was used to detect the secretion of Abeta protein in cell supernatant. Compared with the normal group, the high glucose group showed increase in the p/tGSK3beta protein ratio and the secretion of Abeta protein and decrease in IDE protein and mRNA (P < 0.05). Compared with the high glucose group, both Rb1 and LiCl groups showed decrease in the p/tGSK3beta protein ratio and the expression of Abeta protein and increase in IDE protein and mRNA expression (P < 0.05). Compared with the LiCl group, the Rb1 group showed no significant difference in the expressions of p/tGSK3beta protein, IDE protein, mRNA and Abeta protein expression. In addition, the GSK3beta mRNA expression of the four groups had no significant difference. Ginsenoside Rb1 may reduce the secretion of Abeta protein in hippocampal neurons by reducing the phosphorylation of GSK3beta, down-regulating the ratio of pGSK3beta/GSK3beta and upregulating the expression of IDE.

In 2001, The United States Institute of Medicine (IOM) Committee on Understanding the Biology of Sex and Gender Differences concluded that ‘Sex…should be considered when designing and analysing studies in all areas and at all levels of biomedical and health-related research…’ and stated an apparent paradox i.e.: ‘every cell has a sex’ 1. Sex is defined as ‘the classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement’ whereas gender is defined as ‘a person's self representation as male or female, or how that person is responded to by social institutions based on the individual's gender presentation. Gender is rooted in biology and shaped by environment and experience’ 1.&#13;\n&#13;\nIt is unchallenged that there are health differences between males and females and that social and cultural factors could contribute to the observed differences. Anyway, the sex-dependent differences also have a biological base which sometimes has not been deeply investigated. Scientists studying health differences between male and female aim to both considering social/cultural environment and investigating biological/molecular mechanisms different between sexes. Some experimental studies have elucidated important differences in cell death control 2. A sex disparity, in fact, has been shown both in the propensity to apoptosis and in the activation of the autophagic pathway. In the context of cell fate control, hormones represent important regulators of both apoptosis and autophagy. In the cardiovascular system, for example, oestrogens inhibit cardiomyocyte apoptosis by decreasing reactive oxygen species production and increasing intracellular antioxidants 3. Oestrogens may also indirectly control autophagy as they up-regulate urocortin 4, a neuropeptide hormone able to inhibiting autophagy in cardiomyocytes. Conversely, increasing evidence suggests possible adverse effects of androgens on the vasculature showing that androgens, as opposed to oestrogens, may worsen vascular dysfunction in men, thus contributing to sex-based differences in cardiovascular diseases 5.&#13;\n&#13;\nHowever, it is currently emerging that some cell death programs are differentially controlled by sex-related hormone-independent cellular genetics. Differences in cell death sensitivity in male and female may then occur in the absence of an hormonal context. This is not an immediately obvious finding; Penaloza C et al., 6 have shown that the apoptosis amount differs between the sexes in isolated embryonic cells exposed to similar conditions and this happens at embryonal stages where there are no hormonal influences. Previous studies had reported a sexual dimorphism in embryonic neuronal signal transduction pathways and consequently differences in cell survival 7. Death pathways in XX and XY cells have been poorly investigated as most studies have been performed on established cells lines often irrespective of their male or female origin. Recently, using freshly isolated cells from male and female individuals gave important information on sex disparity in cell fate control. Such sex specificity has been in part clarified thanks to cell culture models where sex steroids can be removed from the media. Even sex-related differences in caspase activation have been found to be independent on hormone exposure. More in detail, cell death occurring in cortical neurons after ischaemia proceeds predominantly via an apoptosis-inducing factor-dependent pathway (a caspase-independent pathway) in male neurons while proceeds via a cytochrome C-dependent pathway (a process mediated by caspase activation) in female neurons 8. In this context, a sex-specific microRNA expression after ischaemia has been described in in vivo studies. In particular, it has been demonstrated that microRNA-23a, by binding the mRNA of the caspase inhibitor named XIAP, induces its translational repression in females, leading to enhanced caspase signalling in the ischaemic female brain. This effect has been shown to be independent of circulating oestrogen levels 9. Sex differences in ischaemic brain injury and cerebrovascular regulation have been observed in clinical and experimental studies and an important determinant of such differences is also represented by the integrity of endothelial cells. In fact, endothelial function is improved in women compared with men, contributing to female cellular higher resistance after ischaemic brain injury. Gupta NC et al. 10 showed that female cerebrovascular endothelial cells express lower level of soluble epoxide hydrolase and consequently have higher levels of vasoprotective epoxyeicosatrienoic acids as compared with male endothelial cells. This study therefore presents a novel additional mechanism underlying differences between male and female cells in apoptotic response after oxygen-glucose deprivation, contributing to explain higher resistance observed in females as compared with males. This study remarks again that differences between male and female cells do not necessarily depend on the hormonal context but may be inherent the cells. We believe that this apparently paradoxical concept has not been sufficiently highlighted in the scientific literature. The present ‘Letter to the Editor’ therefore aims at underlining such an important issue which deserves more attention and discussion in the researchers' community. A practical consequence of sex-dependent discrepancies in cell death control is that cellular response to any stimulus or treatment, in any physiological or pathological context, may well depend on the sex of the cell line used; journals guidelines should therefore require authors to state in any case the sex of the cell lines used in any in vitro study. In addition, at least to some extent, sex-matched or sex-unmatched cell controls may be necessary in many experimental settings. In conclusion, sex-related differences in cell death mechanism may have strong implications for experimental studies and sexual dimorphism dependent on chromosomal rather than hormonal differences have important implications for planning preclinical studies and clinical interventions.

Multiple protein kinases affect the responses of dorsal horn neurons through phosphorylation of synaptic receptors and proteins involved in intracellular signal transduction pathways, and the consequences of this modulation may be spinal central sensitization. In contrast, the phosphatases catalyze an opposing reaction of de-phosphorylation, which may also modulate the functions of crucial proteins in signaling nociception. This is an important mechanism in the regulation of intracellular signal transduction pathways in nociceptive neurons. Accumulated evidence has shown that phosphatase 2A (PP2A), a serine/threonine specific phosphatase, is implicated in synaptic plasticity of the central nervous system and central sensitization of nociception. Therefore, targeting protein phosphotase 2A may provide an effective and novel strategy for the treatment of clinical pain. This review will characterize the structure and functional regulation of neuronal PP2A and bring together recent advances on the modulation of PP2A in targeted downstream substrates and relevant multiple nociceptive signaling molecules.

We developed a mathematical model of a hypothetical neuronal signal transduction pathway to better understand olfactory perception in Caenorhabditis elegans. This worm has only three pairs of olfactory receptor neurons. Intracellular Ca2+ decreases in one pair of olfactory neurons in C. elegans, the AWC neurons, following application of an attractive odor and there is a transient increase in intracellular Ca2+ following removal of odor. The magnitude of this increase is positively correlated with the duration of odor stimulation. Additionally, this Ca2+ transient is induced by a cGMP second messenger system. We identified likely candidates for the signal transduction molecules functioning in this system based on available gene expression and physiological data from AWCs. Our model incorporated a G-protein-coupled odor receptor, a G-protein, a guanylate cyclase as the G-protein effector, and a single phosphodiesterase. Additionally, a cyclic-nucleotide-gated ion channel and a voltage-gated ion channel that mediated calcium influx were incorporated into the model. We posited that, upon odor stimulation, guanylate cyclase was suppressed by the G-protein and that, upon cessation of the stimulus, the G-protein–induced suppression ceased and cGMP synthesis was restored. A key element of our model was a Ca2+-dependent negative feedback loop that ensured that the calcium increases were transient. Two guanylate cyclase-activating proteins acted on the effector guanylate cyclase to negatively regulate cGMP signaling and the resulting calcium influx. Our model was able to closely replicate in silico three important features of the calcium dynamics of AWCs. Specifically, in our simulations, [Ca2+] increased rapidly and reached its peak within 10 s after the odor stimulus was removed, peak [Ca2+] increased with longer odor exposure, and [Ca2+] decreased during a second stimulus that closely followed an initial stimulus. However, application of random background signal (‘noise’) showed that certain components of the pathway were particularly sensitive to this noise.

Objective To investigate the effect of heme oxygenase-1 (HO-1) on cyclin-dependent kinase 5 (CDK5)-ataxia telangiectasia mutated (ATM)-P53 signal transduction pathway in rat hippocampal neurons subjected to oxygen-glucose deprivation (OGD) injury.Methods Hippocampal neurons of newborn Wistar rats ( ＜ 48 h) were cultured for 7 days in vitro.The primary cultured neurons were randomly divided into 4 groups with 10 wells in each group:control group (group C),OGD (group D),OGD + hemin (HO-1 inducer) group (group D + H ) and OGD + hemin + zinc protoporphyrin ( HO-1 inhibitor) group ( group D + H + T).For OGD experiments,cultures were washed three times in a glucose-free balanced salt solution (BSS).They were then placed in deoxygenated glucose-free medium and sealed under 95％ N2-5％ CO2 in an anaerobic chamber equilibrated to 37°C and 100％ humidity for 45 min.OGD was terminated by replacement of stored medium and by returning the cultures to a standard incubator maintained at 37 ℃ in 95％ air-5％ CO2.The OGD model was established after the neurons were preconditioned with hemin 10 μmol/L for 24 h in group D + H.The OGD model was established after the neurons were preconditioned with hemin 10 μmol/L and zinc protoporphyrin 10 μmol/L for 24 h in group D + H + T.After 24 h of culture,the neuronal viability,apoptosis rate,and expression of HO-1 mRNA and protein,and CDK5,ATM and P53 protein were detected.Results Compared with group C,the expression of HO-1 mRNA,and HO-1,CDK5,ATM and P53 protein was up-regulated,the neuronal viability was significantly decreased,and the apoptosis rate was significantly increased in group D (P ＜ 0.01 ).Compared with group D,the expression of HO-1 mRNA and protein was up-regulated,the expression of CDK5,ATM and P53 protein was down-regulated,the neuronal viability was significantly increased,and the apoptosis rate was significanlly decreased in group D + H ( P ＜ 0.01 ).Compared with group D + H,the expression of HO-1 mRNA and protein was down-regulated,the expression of CDK5,ATM and P53 protein was up-regulated,the neuronal viability was significantly decreased,and the apoptosis rate was significantly increased in group D + H + T ( P ＜ 0.01 ).Conclusion HO-1 can inhibit neuronal apoptosis through blocking CDK5-ATM-P53 signal transduction pathway in rat hippocampal neurons subjected to OGD injury. Key words: Heme oxygenase-1; Anoxia; Hippocampus; Neurons; Cyclin-dependent kinase 5; Ataxia telangiectasia; Genes; Genes,p53

Cell death and dysfunction after traumatic brain injury (TBI) is caused by a primary phase, related to direct mechanical disruption of the brain, and a secondary phase which consists of delayed events initiated at the time of the physical insult. Arguably, the calcium ion contributes greatly to the delayed cell damage and death after TBI. A large, sustained influx of calcium into cells can initiate cell death signaling cascades, through activation of several degradative enzymes, such as proteases and endonucleases. However, a sustained level of intracellular free calcium is not necessarily lethal, but the specific route of calcium entry may couple calcium directly to cell death pathways. Other sources of calcium, such as intracellular calcium stores, can also contribute to cell damage. In addition, calcium-mediated signal transduction pathways in neurons may be perturbed following injury. These latter types of alterations may contribute to abnormal physiology in neurons that do not necessarily die after a traumatic episode. This review provides an overview of experimental evidence that has led to our current understanding of the role of calcium signaling in death and dysfunction following TBI.

Role of activating transcription factor 3 in ischemic penumbra region following transient middle cerebral artery occlusion and reperfusion injury