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41.
42.
p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway 总被引:1,自引:0,他引:1
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Sachs BD Baillie GS McCall JR Passino MA Schachtrup C Wallace DA Dunlop AJ MacKenzie KF Klussmann E Lynch MJ Sikorski SL Nuriel T Tsigelny I Zhang J Houslay MD Chao MV Akassoglou K 《The Journal of cell biology》2007,177(6):1119-1132
Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75NTR to enhance cAMP degradation. The p75NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75NTR-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75NTR regulates degradation of cAMP and perpetuates scar formation after injury. 相似文献
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44.
Behavioral phenotypes of Disc1 missense mutations in mice 总被引:6,自引:0,他引:6
Clapcote SJ Lipina TV Millar JK Mackie S Christie S Ogawa F Lerch JP Trimble K Uchiyama M Sakuraba Y Kaneda H Shiroishi T Houslay MD Henkelman RM Sled JG Gondo Y Porteous DJ Roder JC 《Neuron》2007,54(3):387-402
To support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse Disc1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness. 相似文献
45.
Glutamate produces both fast excitation through activation of ionotropic receptors and slower actions through metabotropic receptors (mGluRs). To date, ionotropic but not metabotropic neurotransmission has been shown to undergo long-term synaptic potentiation and depression. Burst stimulation of parallel fibers releases glutamate, which activates perisynaptic mGluR1 in the dendritic spines of cerebellar Purkinje cells. Here, we show that the mGluR1-dependent slow EPSC and its coincident Ca transient were selectively and persistently depressed by repeated climbing fiber-evoked depolarization of Purkinje cells in brain slices. LTD(mGluR1) was also observed when slow synaptic current was evoked by exogenous application of a group I mGluR agonist, implying a postsynaptic expression mechanism. Ca imaging further revealed that LTD(mGluR1) was expressed as coincident attenuation of both limbs of mGluR1 signaling: the slow EPSC and PLC/IP3-mediated dendritic Ca mobilization. Thus, different patterns of neural activity can evoke LTD of either fast ionotropic or slow mGluR1-mediated synaptic signaling. 相似文献
46.
Solignac M Zhang L Mougel F Li B Vautrin D Monnerot M Cornuet JM Worley KC Weinstock GM Gibbs RA 《Genome biology》2007,8(3):403
Two independent genome projects for the honey bee, a microsatellite linkage map and a genome sequence assembly, interactively produced an almost complete organization of the euchromatic genome. Assembly 4.0 now includes 626 scaffolds that were ordered and oriented into chromosomes according to the framework provided by the third-generation linkage map (AmelMap3). Each construct was used to control the quality of the other. The co-linearity of markers in the sequence and the map is almost perfect and argues in favor of the high quality of both. 相似文献
47.
Kirsty J. MacLeod Kevin D. Kohl Brian K. Trevelline Tracy Langkilde 《Molecular ecology》2022,31(1):185-196
The vertebrate gut microbiota (bacterial, archaeal and fungal communities of the gastrointestinal tract) can have profound effects on the physiological processes of their hosts. Although relatively stable, changes in microbiome structure and composition occur due to changes in the environment, including exposure to stressors and associated increases in glucocorticoid hormones. Although a growing number of studies have linked stressor exposure to microbiome changes, few studies have experimentally explored the specific influence of glucocorticoids on the microbiome in wild animals, or across ecologically important processes (e.g., reproductive stages). Here we tested the response of the gut microbiota of adult female Sceloporus undulatus across gestation to ecologically relevant elevations of a stress-relevant glucocorticoid hormone (CORT) in order to determine (i) how experimentally elevated CORT influenced microbiome characteristics, and (ii) whether this relationship was dependent on reproductive context (i.e., whether females were gravid or not, and, in those that were gravid, gestational stage). We show that the effects of CORT on gut microbiota are complex and depend on both gestational state and stage. CORT treatment altered microbial community membership and resulted in an increase in microbiome diversity in late-gestation females, and microbial community membership varied according to treatment. In nongravid females, CORT treatment decreased interindividual variation in microbial communities, but this effect was not observed in late-gestation females. Our results highlight the need for a more holistic understanding of the downstream physiological effects of glucocorticoids, as well as the importance of context (here, gestational state and stage) in interpreting stress effects in ecology. 相似文献
48.
Larry Lüer Anne-Marie Carey Sarah Henry Margherita Maiuri Kirsty Hacking Dario Polli Giulio Cerullo Richard?J. Cogdell 《Biophysical journal》2015,109(9):1885-1898
Allochromatium vinosum (formerly Chromatium vinosum) purple bacteria are known to adapt their light-harvesting strategy during growth according to environmental factors such as temperature and average light intensity. Under low light illumination or low ambient temperature conditions, most of the LH2 complexes in the photosynthetic membranes form a B820 exciton with reduced spectral overlap with LH1. To elucidate the reason for this light and temperature adaptation of the LH2 electronic structure, we performed broadband femtosecond transient absorption spectroscopy as a function of excitation wavelength in A. vinosum membranes. A target analysis of the acquired data yielded individual rate constants for all relevant elementary energy transfer (ET) processes. We found that the ET dynamics in high-light-grown membranes was well described by a homogeneous model, with forward and backward rate constants independent of the pump wavelength. Thus, the overall B800→B850→B890→ Reaction Center ET cascade is well described by simple triexponential kinetics. In the low-light-grown membranes, we found that the elementary backward transfer rate constant from B890 to B820 was strongly reduced compared with the corresponding constant from B890 to B850 in high-light-grown samples. The ET dynamics of low-light-grown membranes was strongly dependent on the pump wavelength, clearly showing that the excitation memory is not lost throughout the exciton lifetime. The observed pump energy dependence of the forward and backward ET rate constants suggests exciton diffusion via B850→ B850 transfer steps, making the overall ET dynamics nonexponential. Our results show that disorder plays a crucial role in our understanding of low-light adaptation in A. vinosum. 相似文献
49.
Serena C. Hedgepeth M. Iveth Garcia Larry E. Wagner II Ana M. Rodriguez Sree V. Chintapalli Russell R. Snyder Gary D. V. Hankins Beric R. Henderson Kirsty M. Brodie David I. Yule Damian B. van Rossum Darren Boehning 《The Journal of biological chemistry》2015,290(11):7304-7313
The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influences many signaling pathways, including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binding directly sensitizes the IP3R to its ligand, IP3. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and, in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCA1 C terminus domain of BRCA1. These findings provide a mechanistic explanation by which BRCA1 can act as a proapoptotic protein. 相似文献
50.
DISC1 at 10: connecting psychiatric genetics and neuroscience 总被引:1,自引:0,他引:1
Psychiatric genetics research, as exemplified by the DISC1 gene, aspires to inform on mental health etiology and to suggest improved strategies for intervention. DISC1 was discovered in 2000 through the molecular cloning of a chromosomal translocation that segregated with a spectrum of major mental illnesses in a single large Scottish family. Through in vitro experiments and mouse models, DISC1 has been firmly established as a genetic risk factor for a spectrum of psychiatric illness. As a consequence of its protein scaffold function, the DISC1 protein impacts on many aspects of brain function, including neurosignaling and neurodevelopment. DISC1 is a pathfinder for understanding psychopathology, brain development, signaling and circuitry. Although much remains to be learnt and understood, potential targets for drug development are starting to emerge, and in this review, we will discuss the 10 years of research that has helped us understand key roles of DISC1 in psychiatric disease. 相似文献