bluuebunny/crossref_metadata_2025_split huggingface dataset:
NAC1, a cocaine‐regulated POZ/BTB protein interacts with CoREST
Authors: Korutla Laxminarayana , Degnan Ryan , Wang Peijie , Mackler Scott A. 
Published: January 2007

AbstractIn this report, CoREST was identified as a protein that interacts with NAC1. NAC1 is a cocaine‐regulated Pox virus and Zinc finger/Bric‐a‐brac Tramtrack Broad complex (POZ/BTB) repressor protein, which mediates interactions among several other transcriptional regulators. In the present study, an interaction between NAC1 and CoREST was detected in neuro‐2A cells and HEK293T cells. We found that the POZ/BTB domain is necessary and sufficient for interaction with CoREST. Surprisingly, only one of five mutations in the POZ/BTB domain that disrupts homodimer assembly interfered with NAC1 and CoREST interactions. These results indicate that POZ/BTB homodimer formation is not required for NAC1–CoREST interaction. CoREST demonstrated protein–protein interactions with both isoforms of NAC1, sNAC1, and lNAC1. Coimmunoprecipitation studies show that NAC1 and CoREST are physically bound together. To further support the results, a direct interaction was demonstrated in glutathione‐S‐transferase pull down assays. siRNA directed against NAC1 mRNA significantly reduced NAC1 protein expression and resulted in reversal of CoREST‐mediated repression in cells. This interaction between NAC1 and CoREST was not found for other POZ/BTB proteins tested. Endogenous interaction was demonstrated in lysates from rat brain samples. This is the first report to demonstrate that a POZ/BTB protein interacts with CoREST. Taken together, the results indicate that CoREST may be part of the NAC1 repressor mechanism.
Extracellular cAMP inhibits D1 dopamine receptor expression in CAD catecholaminergic cells via A2a adenosine receptors
Authors: Do Thuy , Sun Qian , Beuve Annie , Kuzhikandathil Eldo V. 
Published: January 2007

AbstractThe expression of D1 dopamine (DA) receptor gene is regulated during development, aging, and pathophysiology. The extracellular factors and signaling mechanisms that modulate the expression of D1 DA receptor have not been well characterized. Here, we present novel evidence that endogenous D1 DA receptor expression is inhibited by extracellular cAMP in the Cath.A Derived (CAD) catecholaminergic neuronal cell line. CAD cells express the multi‐drug resistance protein 5 transporters and secrete cAMP. Addition of exogenous cAMP decreases D1 receptor mRNA and protein greater than fourfold in 24 h. The cAMP‐induced decrease of D1 receptor mRNA levels is blocked by cGMP and by 1,3‐dipropyl‐8‐(p‐sulfo‐phenyl)xanthine, an inhibitor of ecto‐phosphodiestrase. Extracellular AMP, a metabolite of cAMP, also independently decreased D1 receptor mRNA levels. Inhibitors of ecto‐nucleotidases, α,β‐methyleneadenosine 5′‐di‐phosphate and GMP, completely blocked the decrease of D1 receptor mRNA by extracellular cAMP, but only partially blocked the decrease induced by extracellular AMP. Levamisole, an inhibitor of tissue non‐specific alkaline phosphatase, completely blocked the AMP‐induced decrease of D1 receptor mRNA. The extracellular cAMP, AMP, and adenosine (ADO)‐induced decrease in D1 receptor mRNA expression are mediated by A2a ADO receptor subtype. The results suggest a novel molecular mechanism linking activation of A2a ADO receptors with inhibition of D1 DA receptor expression.
Cyclin D1, cdk4, and Bim are involved in thrombin‐induced apoptosis in cultured cortical neurons
Authors: Rao Haripriya Vittal , Thirumangalakudi Lakshmi , Desmond Paula , Grammas Paula 
Published: January 2007

AbstractThrombin, a multifunctional serine protease, is neurotoxic in vitro and in vivo. Thrombin has been shown to be increased in Alzheimer’s disease (AD) and other neuropathological conditions and could be a mediator of pathological neuronal cell death in the brain. The mechanisms of thrombin‐induced neuronal cell death are incompletely understood. The objective of this study is to explore mechanisms that contribute to thrombin‐induced neuronal apoptosis focusing on the role of cell cycle regulators and the pro‐apoptotic protein Bim (Bcl‐2‐interacting mediator of cell death) in this process. Our data show that thrombin treatment of primary cerebral cortical cultures results in dose‐dependent apoptotic cell death. Exposure of neuronal cultures to thrombin leads to induction of cell cycle proteins cyclin D1 and cyclin E, at both mRNA and protein levels. In addition, thrombin treatment causes the appearance of cyclin‐dependent kinase 4 (cdk4) and expression of the pro‐apoptotic protein Bim. Inhibition of cdk4 prevents both induction of Bim expression and thrombin‐induced neuronal apoptosis. These data demonstrate that thrombin‐induced apoptosis proceeds via cell cycle activation involving cdk4 resulting in induction of Bim. Thus, cell cycle proteins could be therapeutic targets in diseases such as AD where thrombin has been implicated.
The requirement of Ras and Rap1 for the activation of ERKs by cAMP, PACAP, and KCl in cerebellar granule cells
Authors: Obara Yutaro , Horgan Angela M. , Stork Philip J. S. 
Published: January 2007

AbstractIn cerebellar granule cells, the mitogen‐activated protein kinase (MAPK) or extracellular signal‐regulated kinase (ERK) cascade mediates multiple functions, including proliferation, differentiation, and survival. In these cells, ERKs are activated by diverse stimuli, including cyclic adenosine monophosphate (cAMP), pituitary adenylate cyclase activating protein (PACAP), depolarization induced by elevated extracellular potassium (KCl), and the neurotrophin brain‐derived neurotrophic factor. Extensive studies in neuronal cell lines have implicated the small G proteins Ras and Rap1 in the activation of ERKs by cAMP, PACAP, and KCl. However, the requirement of Ras and Rap1 in these pathways in cerebellar granule cells has not been addressed. In this study, we utilize multiple biochemical assays to determine the mechanisms of action and requirement of Ras and Rap1 in cultured cerebellar granule cells. We show that both Ras and Rap1 can be activated by cAMP or PACAP via protein kinase (PKA)‐dependent mechanisms. KCl activation of Ras also required PKA. Using both adenoviral and transgenic approaches, we show that Ras plays a major role in ERK activation by cAMP, PACAP, and KCl, while Rap1 also mediates activation of a selective membrane‐associated pool of ERKs. Furthermore, Rap1, but not Ras, activation by PKA appears to require the action of Src family kinases.
FAD mutants unable to increase neurotoxic Aβ 42 suggest that mutation effects on neurodegeneration may be independent of effects on Aβ
Authors: Shioi Junichi , Georgakopoulos Anastasios , Mehta Pankaj , Kouchi Zen , Litterst Claudia M. , Baki Lia , Robakis Nikolaos K. 
Published: January 2007

AbstractStrong support for a primary causative role of the Aβ peptides in the development of Alzheimer’s disease (AD) neurodegeneration derives from reports that presenilin familial AD (FAD) mutants alter amyloid precursor protein processing, thus increasing production of neurotoxic Aβ 1–42 (Aβ 42). This effect of FAD mutants is also reflected in an increased ratio of peptides Aβ 42 over Aβ 1–40 (Aβ 40). In the present study, we show that several presenilin 1 FAD mutants failed to increase production of Aβ 42 or the Aβ 42/40 ratio. Our data suggest that the mechanism by which FAD mutations promote neurodegeneration and AD may be independent of their effects on Aβ production.
Serotonin transporter function, but not expression, is dependent on brain‐derived neurotrophic factor (BDNF): in vivo studies in BDNF‐deficient mice
Authors: Daws L. C. , Munn J. L. , Valdez M. F. , Frosto‐Burke T. , Hensler J. G. 
Published: January 2007

AbstractIn the present study, we used high‐speed chronoamperometry to examine serotonin (5‐HT) transporter (5‐HTT) function in vivo in 2‐, 5‐, and 10‐month‐old brain‐derived neurotrophic factor (BDNF)+/− mice. The rate of clearance of exogenously applied 5‐HT was measured in CA3 region of hippocampus. In 2‐month‐old mice, the rate of 5‐HT clearance did not differ between BDNF+/+ and BDNF+/− mice. In BDNF+/+ mice, 5‐HT clearance rate (Tc) increased markedly with age. In contrast, Tc remained relatively static in BDNF+/− mice across 2‐, 5‐, and 10‐month age groups. At 5 months of age, female BDNF+/+ mice had a lower maximal velocity (Vmax) for 5‐HT clearance than male BDNF+/+ mice. There was a similar trend in 5‐month‐old BDNF+/− mice, but this did not reach statistical significance. There was an age‐dependent increase in KT value for 5‐HT clearance (i.e., decreased in vivo affinity of 5‐HTT), but no significant effect of genotype or gender. 5‐HTT density, as measured by [3H]cyanoimipramine binding, was not different between BDNF+/+ and BDNF+/− mice, although there was a significant increase in 5‐HTT binding with age. The selective 5‐HT reuptake inhibitor fluvoxamine (50 and 100 pmol) significantly decreased 5‐HT clearance in BDNF+/+ mice, but not in BDNF+/− mice. Our data suggest that the profoundly reduced ability of 5‐ and 10‐month‐old BDNF+/− mice to clear 5‐HT is not because of a decrease in the total number of 5‐HTTs, but may be due to functional deficits in the 5‐HTT, e.g., in the machinery/signaling required for insertion of 5‐HTTs into the plasma membrane and/or activation of the 5‐HTT once it is positioned to take up 5‐HT from extracellular fluid.
Phospholipase C‐related inactive protein is implicated in the constitutive internalization of GABAAreceptors mediated by clathrin and AP2 adaptor complex
Authors: Kanematsu Takashi , Fujii Makoto , Mizokami Akiko , Kittler Josef T. , Nabekura Junichi , Moss Stephen J. , Hirata Masato 
Published: January 2007

AbstractA mechanism for regulating the strength of synaptic inhibition is enabled by altering the number of GABAAreceptors available at the cell surface. Clathrin and adaptor protein 2 (AP2) complex‐mediated endocytosis is known to play a fundamental role in regulating cell surface GABAAreceptor numbers. Very recently, we have elucidated that phospholipase C‐related catalytically inactive protein (PRIP) molecules are involved in the phosphorylation‐dependent regulation of the internalization of GABAAreceptors through association with receptor β subunits and protein phosphatases. In this study, we examined the implications of PRIP molecules in clathrin‐mediated constitutive GABAAreceptor endocytosis, independent of phospho‐regulation. We performed a constitutive receptor internalization assay using human embryonic kidney 293 (HEK293) cells transiently expressed with GABAAreceptor α/β/γ subunits and PRIP. PRIP was internalized together with GABAAreceptors, and the process was inhibited by PRIP‐binding peptide which blocks PRIP binding to β subunits. The clathrin heavy chain, μ2 and β2 subunits of AP2 and PRIP‐1, were complexed with GABAAreceptor in brain extract as analyzed by co‐immunoprecipitation assay using anti‐PRIP‐1 and anti‐β2/3 GABAAreceptor antibody or by pull‐down assay using β subunits of GABAAreceptor. These results indicate that PRIP is primarily implicated in the constitutive internalization of GABAAreceptor that requires clathrin and AP2 protein complex.
Anxiety induced by prenatal stress is associated with suppression of hippocampal genes involved in synaptic function
Authors: Bogoch Y. , Biala Y. N. , Linial M. , Weinstock M. 
Published: January 2007

AbstractExposure of pregnant women or animals to stress during a critical period of foetal brain development increases the likelihood of anxiety, depression and learning deficits that are associated with structural alterations in the offspring hippocampus. In this study, we report the effect of gestational stress in rats on anxiogenic behaviour and hippocampal gene expression of their 23‐day‐old female offspring. As the rat brain continues to develop after birth, we also used the procedure of handling (H) during the first 10 days of life to reverse the anxiogenic behaviour of prenatally stressed (PS) rats. By means of micro‐array analysis on hippocampal extracts, we found that the expression of about 6.1% of 9505 valid genes was significantly altered by prenatal stress (p < 0.05). Of these, 48% were over‐expressed and 52% under‐expressed. The latter included ∼300 genes that participate in axonal growth, regulation of ion channels and transporters, trafficking of synaptic vesicles and neurotransmitter release. About 30% of the genes that were down‐regulated in PS rats were restored to control levels by H. These include genes that play a role in pre‐synaptic organization and function. Our results provide a possible relationship between hippocampal gene expression and changes in behaviour resulting from prenatal stress.
Visualization of 2‐arachidonoylglycerol accumulation and cannabinoid CB1 receptor activity in rat brain cryosections by functional autoradiography
Authors: Palomäki Ville A. B. , Lehtonen Marko , Savinainen Juha R. , Laitinen Jarmo T. 
Published: January 2007

AbstractIn neuronal signalling mediated by the endocannabinoid 2‐arachidonoylglycerol, both synthetic and inactivating enzymes operate within close proximity to the Gi/o‐coupled pre‐synaptic CB1 receptors, thus allowing for rapid onset and transient duration of this lipid modulator. In rat brain, 2‐arachidonoylglycerol is inactivated mainly via hydrolysis by serine hydrolase inhibitor‐sensitive monoacylglycerol lipase activity. We show in this study that comprehensive pharmacological elimination of this activity in brain cryosections by methyl arachidonylfluorophosphonate or hexadecylsulphonyl fluoride results in endocannabinoid‐mediated CB1 receptor activity, which can be visualized by functional autoradiography. URB597, a specific inhibitor of anandamide hydrolysis proved ineffective. TLC indicated that the bioactivity resided in 2‐arachidonoylglycerol‐containing fraction and gas chromatography–mass spectroscopy detected elevated levels of monoacylglycerols, including 2‐arachidonoylglycerol in this fraction. Although two diacylglycerol lipase inhibitors, tetrahydrolipstatin (THL) and RHC80267, blocked the bulk of 2‐arachidonoylglycerol accumulation in methyl arachidonylfluorophosphonate‐treated sections, only THL reversed the endocannabinoid‐dependent CB1 receptor activity. Further studies indicated that at the used concentrations, THL rather specifically antagonized the CB1 receptor. These findings confirm that in brain sections there is preservation of enzymatic pathways regulating the production of endogenous receptor ligands. Furthermore, the presently described methodology may serve as an elegant and intuitive approach to identify novel membrane‐derived lipid modulators operating in the CNS.
Recognition molecules and neural repair
Authors: Loers Gabriele , Schachner Melitta 
Published: January 2007

AbstractNeural recognition molecules were discovered and characterized initially for their functional roles in cell adhesion as regulators of affinity between cells and the extracellular matrix in vitro. They were then recognized as mediators or co‐receptors which trigger signal transduction mechanisms affecting cell adhesion and de‐adhesion. Their involvement in contact attraction and repulsion relies on cell‐intrinsic properties that are modulated by the spatial contexts of their expression at particular stages of ontogenetic development, in synaptic plasticity and during regeneration after injury. The functional roles of recognition molecules in cell proliferation and migration, determination of developmental fate, growth cone guidance, and synapse formation, stabilization and modulation have been well documented not only by in vitro, but also by in vivo studies that have been greatly aided by generation of genetically altered mice. More recently, the functions of recognition molecules have been investigated under conditions of neural repair and manipulated using a broad range of genetic and pharmacological approaches to achieve a beneficial outcome. The principal aim of most therapeutically oriented approaches has been to neutralize inhibitory factors. However, less attention has been paid to enhancing repair by stimulating the stimulatory factors. When considering potential therapeutic strategies, it is worth considering that a single recognition molecule can possess domains that are conducive or repellent and that the spatial distribution of recognition molecules can determine the overall function: Recognition molecules may be repellent for neurite outgrowth when presented as barriers or steep‐concentration gradients and conducive when presented as uniform substrates. The focus of this review will be on the more recent attempts to study the conducive mechanisms with the expectation that they may be able to tip the balance from a regeneration inhospitable to a hospitable environment. It is likely that a combination of the two principles, as multifactorial as each principle may be in itself, will be of therapeutic value in humans.
Neuroprotective actions of a histidine analogue in models of ischemic stroke
Authors: Tang Sung‐Chun , Arumugam Thiruma V. , Cutler Roy G. , Jo Dong‐Gyu , Magnus Tim , Chan Sic L. , Mughal Mohamed R. , Telljohann Richard S. , Nassar Matthew , Ouyang Xin , Calderan Andrea , Ruzza Paolo , Guiotto Andrea , Mattson Mark P. 
Published: January 2007

AbstractHistidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4‐hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase‐3 protein. These findings suggest a therapeutic potential for HNE‐scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions.
Identification of IRAS/Nischarin as an I1‐imidazoline receptor in PC12 rat pheochromocytoma cells
Authors: Sun Zheng , Chang Chung‐Ho , Ernsberger Paul 
Published: January 2007

AbstractThe I1‐imidazoline receptor (I1R) is a proposed target for drug action relevant to blood pressure and glucose control. The imidazoline receptor antisera‐selected (IRAS) gene, also known as Nischarin, has several characteristics of an I1R. To test the contribution of IRAS to I1R binding capacity and cell‐signaling function, an antisense probe targeting the initiating codon of rat IRAS gene was evaluated in PC12 rat pheochromocytoma cells, a well‐established model for I1R action. The density of I1R was significantly reduced by antisense compared with control transfection (Bmax = 400 ± 16 vs. 691 ± 29 fmol/mg protein), without significantly affecting binding affinity (Kd = 0.30 ± 0.04 vs. 0.39 ± 0.05 nmol/L). Thus, IRAS expression is necessary for high‐affinity binding to I1R. Western blots with polyclonal anti‐IRAS showed reduced IRAS expression in the major 85‐kDa band relative to an actin reference, paralleling the reduction in binding site density. To determine whether reduced IRAS expression attenuated I1R cell signaling, PC12 cells transfected with antisense or sense oligo‐DNA were treated with moxonidine, an I1R agonist, then cell lysates were analyzed by western blot. Dose‐dependent activation of extracellular signal‐regulated kinase was attenuated without affecting the potency of the agonist. In contrast, extracellular signal‐regulated kinase activation by insulin was unchanged. The IRAS gene is likely to encode an I1R or a functional subunit.
β‐Amyloid increases somatostatin expression in cultured cortical neurons
Authors: Geci Catherine , How Jonathan , Alturaihi Haydar , Kumar Ujendra 
Published: January 2007

AbstractIn β‐amyloid (Aβ)‐induced neurotoxicity, activation of the NMDA receptor, increased Ca2+ and oxidative stress are intimately associated with neuronal cell death as normally seen in NMDA‐induced neurotoxicity. We have recently shown selective sparing of somatostatin (SST)‐positive neurons and increased SST expression in NMDA agonist‐induced neurotoxicity. Accordingly, the present study was undertaken to determine the effect of Aβ25–35‐induced neurotoxicity on the expression of SST in cultured cortical neurons. Cultured cortical cells were exposed to Aβ25–35 and processed to determine the cellular content and release of SST into medium by radioimmunoassay and SST mRNA by RT‐PCR. Aβ25–35 induces neuronal cell death in a concentration‐ and time‐dependent fashion, increases SST mRNA synthesis and induces an augmentation in the cellular content of SST. No significant changes were seen on SST release at any concentration of Aβ25–35 after 24 h of treatment. However, Aβ25–35 induces a significant increase of SST release into medium only after 12 h in comparison with other time points. Most significantly, SST‐positive neurons are selectively spared in the presence of a lower concentration of Aβ25–35, whereas, in the presence of higher concentrations of Aβ25–35 for extended time periods, SST‐positive neurons decrease gradually. Furthermore, Aβ25–35 induces apoptosis at lower concentrations (5 and 10 μmol/L) and necrosis at higher concentrations (20 and 40 μmol/L). Consistent with the increased accumulation of SST, these data suggest that Aβ25–35 impairs cell membrane permeability. Selective sparing of SST‐positive neurons at lower concentrations of Aβ25–35 at early time points directly correlates with the pathophysiology of Alzheimer’s disease.
The effect of host plant on larval survivorship of the Alaskan swallowtail butterfly (Papilio machaon aliaska)
Authors: Murphy Shannon M. 
Published: January 2007

AbstractThe Alaskan swallowtail butterfly, Papilio machaon aliaska (Lepidoptera: Papilionidae), uses three plant species as host plants. Cnidium cnidiifolium (Turcz.) Schischk. belongs to the family Apiaceae, the ancestral host‐plant family of the P. machaon group. Artemisia arctica Less. and Petasites frigidus (L.) Franch, in contrast, belong to the distantly related Asteraceae family and were colonized relatively recently by this group of butterflies. Previous work has shown that larval survival is highest on the novel host plants when natural enemies are present in the field. Here I examine whether P. m. aliaska fitness varied when individuals were reared on the three host plants in a common environment, free of environmental and ecological complications such as predation. I collected 12 P. m. aliaska females and measured their reproductive success when their progeny were reared on each of the three host plants. I assessed larval fitness on each of the hosts by recording the percentage pupation and percentage emergence as well as by measuring pupal mass. I found that larvae reared on the ancestral host plant, C. cnidiifolium, had higher fitness than did larvae reared on either of the novel host plants, A. arctica or P. frigidus. Larvae reared on C. cnidiifolium were more likely to pupate, achieved a greater pupal mass, and had higher emergence rates than larvae reared on the novel hosts. I interpret these results to mean that, in the absence of predation, the ancestral host plant is a better host for P. m. aliaska larvae than either novel host and I contend that this result does not appear to support the hypothesis that P. m. aliaska populations in central Alaska are divided into host races.