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51.
Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning. 总被引:6,自引:0,他引:6 下载免费PDF全文
D Balschun D P Wolfer F Bertocchini V Barone A Conti W Zuschratter L Missiaen H P Lipp J U Frey V Sorrentino 《The EMBO journal》1999,18(19):5264-5273
Deletion of the ryanodine receptor type 3 (RyR3) results in specific changes in hippocampal synaptic plasticity, without affecting hippocampal morphology, basal synaptic transmission or presynaptic function. Robust long-term potentiation (LTP) induced by repeated, strong tetanization in the CA1 region and in the dentate gyrus was unaltered in hippocampal slices in vitro, whereas weak forms of plasticity generated by either a single weak tetanization or depotentiation of a robust LTP were impaired. These distinct physiological deficits were paralleled by a reduced flexibility in re-learning a new target in the water-maze. In contrast, learning performance in the acquisition phase and during probe trial did not differ between the mutants and their wild-type littermates. In the open-field, RyR3(-/-) mice displayed a normal exploration and habituation, but had an increased speed of locomotion and a mild tendency to circular running. The observed physiological and behavioral effects implicate RyR3-mediated Ca(2+) release in the intracellular processes underlying spatial learning and hippocampal synaptic plasticity. 相似文献
52.
Hochdörfer T Kuhny M Zorn CN Hendriks RW Vanhaesebroeck B Bohnacker T Krystal G Huber M 《Cellular signalling》2011,23(5):866-875
Recognition of bacterial constituents by mast cells (MCs) is dependent on the presence of pattern recognition receptors, such as Toll-like receptors (TLRs). The final cellular response, however, depends on the influence of multiple environmental factors. In the current study we tested the hypothesis that the PI3K-activating ligands insulin-like growth factor-1 (IGF-1), insulin, antigen, and Steel Factor (SF) are able to modulate the TLR4-mediated production of proinflammatory cytokines in murine MCs. Costimulation with any of these ligands caused increased LPS-triggered secretion of IL-6 and TNF-α, but attenuated the production of IL-1β, though all three cytokines were produced in an NFκB-dependent manner. The pan-specific PI3K-inhibitor Wortmannin reverted the altered production of these cytokines. In agreement, MCs deficient for SHIP1, a negative regulator of the PI3K pathway, showed augmented secretion of IL-6/TNF-α and reduced production of IL-1β in response to LPS alone. The differential effects of IGF-1 on TLR4-mediated cytokine production were also observed in the context of TLR2 and IL-33 receptor-mediated MC activation. Importantly, these effects were seen in both bone marrow-derived and peritoneal MCs, suggesting general relevance for MCs. Using pharmacological and genetic tools, we could show that the p110δ isoform of PI3K is strongly implicated in SF-triggered suppression of LPS-induced IL-1β production. Costimulation with antigen was affected to a lesser extent. In conclusion, NFκB-dependent production of proinflammatory cytokines in MCs is differentially controlled by PI3K-activating ligand/receptor systems. 相似文献
53.
Dode L Andersen JP Raeymaekers L Missiaen L Vilsen B Wuytack F 《The Journal of biological chemistry》2005,280(47):39124-39134
Steady-state and transient kinetic studies were performed to functionally analyze the overall and partial reactions of the Ca(2+) transport cycle of the human secretory pathway Ca(2+)/Mn(2+)-ATPase 1 (SPCA1) isoforms: SPCA1a, SPCA1b, SPCA1c, and SPCA1d (encoded by ATP2C1, the gene defective in Hailey-Hailey disease) upon heterologous expression in mammalian cells. The expression levels of SPCA1 isoforms were 200-350-fold higher than in control cells except for SPCA1c, whose low expression level appears to be the effect of rapid degradation because of protein misfolding. Relative to SERCA1a, the active SPCA1a, SPCA1b, and SPCA1d enzymes displayed extremely high apparent affinities for cytosolic Ca(2+) in activation of the overall ATPase and phosphorylation activities. The maximal turnover rates of the ATPase activity for SPCA1 isoforms were 4.7-6.4-fold lower than that of SERCA1a (lowest for the shortest SPCA1a isoform). The kinetic analysis traced these differences to a decreased rate of the E(1) approximately P(Ca) to E(2)-P transition. The apparent affinity for inorganic phosphate was reduced in the SPCA1 enzymes. This could be accounted for by an enhanced rate of the E(2)-P hydrolysis, which showed constitutive activation, lacking the SERCA1a-specific dependence on pH and K(+). 相似文献
54.
Arctostylopids are enigmatic mammals known from the Paleocene and Early Eocene of Asia and North America. Based on molar similarities, they have most often been grouped with the extinct Notoungulata from South and Central America, but tarsal evidence links them to Asian basal gliriforms. Although Palaeostylops is the best-known arctostylopid genus, some points of its content and species level taxonomy remain uncertain. Here we report 255 upper and lower jaw fragments of Palaeostylops, five calcanea, three astragali, as well as the first known arctostylopid distal tibia. This new material was collected from the late Paleocene of the Flaming Cliffs area in Mongolia, in a single lens almost exclusively containing arctostylopid remains. Our study of the morphology and size of the new Palaeostylops dental material confirms the validity of two species, P. iturus and P. macrodon, and illustrates their morphological and biometrical variability and diagnostic differences. The distal tibia of Palaeostylops is relatively unspecialised and resembles the Asian gliriforms Pseudictops and Rhombomylus. We also review the relevance of the historically important genus Palaeostylops in view of other, more recently described but less abundant arctostylopid genera. Palaeostylops remains the reference taxon for the arctostylopid anterior dentition and postcranial morphology. For both anatomical regions, arctostylopids differ significantly from notoungulates, and present a mosaic of characters also seen in basal gliriforms. The notoungulate-like molars of Palaeostylops are highly specialized for arctostylopids and the arctostylopid molar morphotype is therefore better illustrated by the early middle Paleocene Asiostylops. This morphotype does not present any similarities to notoungulates, but shares a number of derived characters with basal gliriforms. Among gliriforms, the primitive arctostylopid morphotype is most similar to Astigale from the early Paleocene of South China, and we suggest that Arctostylopidae may therefore be more closely related to Astigalidae than to any other group. 相似文献
55.
Michael P Scheid Michael Huber Jacqueline E Damen Michael Hughes Veronica Kang Paul Neilsen Glenn D Prestwich Gerald Krystal Vincent Duronio 《The Journal of biological chemistry》2002,277(11):9027-9035
Using bone marrow derived mast cells from SH2-containing inositol-5-phosphatase (SHIP) +/+ and minus sign/minus sign mice, we found that the loss of SHIP leads to a dramatic increase in Steel Factor (SF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3)), a substantial reduction in PI(3,4)P(2), and no change in PI(4,5)P(2) levels. We also found that SF-induced activation of protein kinase B (PKB) is increased and prolonged in SHIP -/- cells, due in large part to more PKB associating with the plasma membrane in these cells. Pretreatment of SHIP -/- cells with 25 microm LY294002 resulted in complete inhibition of SF-induced PI(3,4)P(2), while still yielding PI(3,4,5)P(3) levels similar to those achieved in SHIP+/+ cells. This offered a unique opportunity to study the regulation of PKB by PI(3,4,5)P(3), in the absence of PI(3,4)P(2). Under these conditions, PKB activity was markedly reduced compared with that in SF-stimulated SHIP+/+ cells, even though more PKB localized to the plasma membrane. Although phosphoinositide-dependent kinase 1 mediated phosphorylation of PKB at Thr-308 was unaffected by LY294002, phosphorylation at Ser-473 was dramatically reduced. Moreover, intracellular delivery of PI(3,4)P(2) to LY294002-pretreated, SF-stimulated SHIP -/- cells increased phosphorylation of PKB at Ser-473 and increased PKB activity. These results are consistent with a model in which SHIP serves as a regulator of both activity and subcellular localization of PKB. 相似文献
56.
57.
Perry S Brignola Karen Lackey Sue H Kadwell Christine Hoffman Earnest Horne H Luke Carter J Darren Stuart Kevin Blackburn Mary B Moyer Krystal J Alligood Wilson B Knight Edgar R Wood 《The Journal of biological chemistry》2002,277(2):1576-1585
Epidermal growth factor receptor (EGFR), ErbB-2, and ErbB-4 are members of the type 1 receptor tyrosine kinase family. Overexpression of these receptors, especially ErbB-2 and EGFR, has been implicated in multiple forms of cancer. Inhibitors of EGFR tyrosine kinase activity are being evaluated clinically for cancer therapy. The potency and selectivity of these inhibitors may affect the efficacy and toxicity of therapy. Here we describe the expression, purification, and biochemical comparison of EGFR, ErbB-2, and ErbB-4 intracellular domains. Despite their high degree of sequence homology, the three enzymes have significantly different catalytic properties and substrate kinetics. For example, the catalytic activity of ErbB-2 is less stable than that of EGFR. ErbB-2 uses ATP-Mg as a substrate inefficiently compared with EGFR and ErbB-4. The three enzymes have very similar substrate preferences for three optimized peptide substrates, but differences in substrate synergies were observed. We have used the biochemical and kinetic parameters determined from these studies to develop an assay system that accurately measures inhibitor potency and selectivity between the type 1 receptor family. We report that the selectivity profile of molecules in the 4-anilinoquinazoline series can be modified through specific aniline substitutions. Moreover, these compounds have activity in whole cells that reflect the potency and selectivity of target inhibition determined with this assay system. 相似文献
58.
L Missiaen Y Kanmura J A Eggermont R Casteels 《Biochemical and biophysical research communications》1989,158(1):302-306
In myometrium from pregnant rats, 100 nM-TPA elevated resting tension and initially slightly enhanced the contraction induced by 138 mM-KCl. After 20 min this force development significantly declined. In saponin-treated skinned myometrial cells from pregnant rats, 100 nM-TPA enhanced the contraction induced by 0.3 microM-Ca2+, but reduced that induced by 1 microM-Ca2+. These findings suggest that the excitatory and inhibitory actions of TPA on the myometrium are probably due to its action on the contractile proteins. In myometrium from non-pregnant rats, TPA affected neither the resting tension, nor the amplitude of the evoked contractions, nor the Ca2+-induced contractions in skinned myometrium. While TPA only affected tension development in pregnant rats, both 1 mM-carbachol and 90 nM-oxytocin induced a tonic contraction in Ca-free solution independently of the hormonal status of the rats. The latter finding makes it unlikely that activation of protein kinase C is involved in the agonist-induced tonic force development in Ca-free solution. 相似文献
59.
Yan Chen Sing-Yuen Sit Jie Chen Jacob J. Swidorski Zheng Liu Ny Sin Brian L. Venables Dawn D. Parker Beata Nowicka-Sans Zeyu Lin Zhufang Li Brian J. Terry Tricia Protack Sandhya Rahematpura Umesh Hanumegowda Susan Jenkins Mark Krystal Ira D. Dicker Alicia Regueiro-Ren 《Bioorganic & medicinal chemistry letters》2018,28(9):1550-1557
The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants. 相似文献
60.