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61.
Catania MV D'Antoni S Bonaccorso CM Aronica E Bear MF Nicoletti F 《Molecular neurobiology》2007,35(3):298-307
Group I metabotropic glutamate receptors (mGlu1 and mGlu5) are coupled to polyphosphoinositide hydrolysis and are involved
in activity-dependent forms of synaptic plasticity, both during development and in the adult life. Group I mGlu receptors
can also regulate proliferation, differentiation, and survival of neural stem/progenitor cells, which further support their
role in brain development. An exaggerated response to activation of mGlu5 receptors may underlie synaptic dysfunction in Fragile
X syndrome, the most common inherited form of mental retardation. In addition, group I mGlu receptors are overexpressed in
dysplastic neurons of focal cortical dysplasia and hemimegaloencephaly, which are disorders of cortical development associated
with chronic epilepsy. Drugs that block the activity of group I mGlu receptors (in particular, mGlu5 receptors) are potentially
helpful for the treatment of Fragile X syndrome and perhaps other neurodevelopmental disorders. 相似文献
62.
Targeting farnesoid X receptor for liver and metabolic disorders 总被引:3,自引:0,他引:3
The farnesoid X receptor (FXR) is a metabolic nuclear receptor expressed in the liver, intestine, kidney and adipose tissue. By regulating the expression and function of genes involved in bile acid (BA) synthesis, uptake and excretion, FXR has emerged as a key gene involved in the maintenance of cholesterol and BA homeostasis. FXR ligands are currently under clinical investigation for the treatment of cholestasis, dyslipidemic disorders and conditions of insulin resistance in type 2 diabetes and non-alcoholic steatohepatitis (NASH). Because activation of FXR impacts a considerable number of genes, development of FXR modulators that selectively regulate specific pathways will limit potentially undesirable side effects. Interaction of FXR with other BAs and xenobiotics sensors such as the constitutive androstane receptor and the pregnane X receptor might allow the development of combination therapies for liver and metabolic disorders. 相似文献
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65.
Aurelio Reyes Laura Melchionda Alessia Nasca Franco Carrara Eleonora Lamantea Alice Zanolini Costanza Lamperti Mingyan Fang Jianguo Zhang Dario Ronchi Sara Bonato Gigliola Fagiolari Maurizio Moggio Daniele Ghezzi Massimo Zeviani 《American journal of human genetics》2015,97(1):186-193
Chronic progressive external ophthalmoplegia (CPEO) is common in mitochondrial disorders and is frequently associated with multiple mtDNA deletions. The onset is typically in adulthood, and affected subjects can also present with general muscle weakness. The underlying genetic defects comprise autosomal-dominant or recessive mutations in several nuclear genes, most of which play a role in mtDNA replication. Next-generation sequencing led to the identification of compound-heterozygous RNASEH1 mutations in two singleton subjects and a homozygous mutation in four siblings. RNASEH1, encoding ribonuclease H1 (RNase H1), is an endonuclease that is present in both the nucleus and mitochondria and digests the RNA component of RNA-DNA hybrids. Unlike mitochondria, the nucleus harbors a second ribonuclease (RNase H2). All affected individuals first presented with CPEO and exercise intolerance in their twenties, and these were followed by muscle weakness, dysphagia, and spino-cerebellar signs with impaired gait coordination, dysmetria, and dysarthria. Ragged-red and cytochrome c oxidase (COX)-negative fibers, together with impaired activity of various mitochondrial respiratory chain complexes, were observed in muscle biopsies of affected subjects. Western blot analysis showed the virtual absence of RNase H1 in total lysate from mutant fibroblasts. By an in vitro assay, we demonstrated that altered RNase H1 has a reduced capability to remove the RNA from RNA-DNA hybrids, confirming their pathogenic role. Given that an increasing amount of evidence indicates the presence of RNA primers during mtDNA replication, this result might also explain the accumulation of mtDNA deletions and underscores the importance of RNase H1 for mtDNA maintenance. 相似文献
66.
Eleonora Corradini Pepijn P. Burgers Michael Plank Albert J. R. Heck Arjen Scholten 《The Journal of biological chemistry》2015,290(12):7887-7896
Protein-protein interactions are important in providing compartmentalization and specificity in cellular signal transduction. Many studies have hallmarked the well designed compartmentalization of the cAMP-dependent protein kinase (PKA) through its anchoring proteins. Much less data are available on the compartmentalization of its closest homolog, cGMP-dependent protein kinase (PKG), via its own PKG anchoring proteins (GKAPs). For the enrichment, screening, and discovery of (novel) PKA anchoring proteins, a plethora of methodologies is available, including our previously described chemical proteomics approach based on immobilized cAMP or cGMP. Although this method was demonstrated to be effective, each immobilized cyclic nucleotide did not discriminate in the enrichment for either PKA or PKG and their secondary interactors. Hence, with PKG signaling components being less abundant in most tissues, it turned out to be challenging to enrich and identify GKAPs. Here we extend this cAMP-based chemical proteomics approach using competitive concentrations of free cyclic nucleotides to isolate each kinase and its secondary interactors. Using this approach, we identified Huntingtin-associated protein 1 (HAP1) as a putative novel GKAP. Through sequence alignment with known GKAPs and secondary structure prediction analysis, we defined a small sequence domain mediating the interaction with PKG Iβ but not PKG Iα. In vitro binding studies and site-directed mutagenesis further confirmed the specificity and affinity of HAP1 binding to the PKG Iβ N terminus. These data fully support that HAP1 is a GKAP, anchoring specifically to the cGMP-dependent protein kinase isoform Iβ, and provide further evidence that also PKG spatiotemporal signaling is largely controlled by anchoring proteins. 相似文献
67.
TRPV1 (transient receptor potential vanilloid 1) proteins are heat-activated nonselective cation channels. TRPV1 channels are polymodal in their function and exhibit multifaceted regulation with various molecular compounds. In this regard, phosphoinositides, particularly phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate, are important channel regulators. However, their effects on TRPV1 channel activity have not been conclusively determined. To characterize temperature-induced activation of TRPV1 in the presence of different phospholipids, we purified the TRPV1 protein from HEK-293 cells and incorporated it into planar lipid bilayers. In the presence of 2.5 μm phosphatidylinositol 4,5-bisphosphate, TRPV1 channels demonstrated rapid activation at 33–39 °C and achieved full channel opening at 42 °C. At this temperature range, TRPV1 heat activation exhibited steep temperature dependence (temperature coefficient (Q10) of 18), and the channel openings were accompanied by large changes in entropy and enthalpy, suggesting a substantial conformation change. At a similar temperature range, another phosphoinositide, phosphatidylinositol 4-phosphate, also potentiated heat activation of TRPV1, but with much lower efficiency. Negatively charged phosphatidylglycerol could also induce heat activation of TRPV1 channels, although with a small-conductance state. Our data demonstrate that phospholipids, specifically phosphoinositides, are important regulators of TRPV1 and are required for heat-induced channel activity. 相似文献
68.
Geometric morphometrics throws light on evolution of the subterranean catfish Rhamdiopsis krugi (Teleostei: Siluriformes: Heptapteridae) in eastern Brazil 下载免费PDF全文
Maria Elina Bichuette Bianca Rantin Erika Hingst‐Zaher Eleonora Trajano 《Biological journal of the Linnean Society. Linnean Society of London》2015,114(1):136-151
Rhamdiopsis krugi is a highly specialized troglobitic (exclusively subterranean) catfish from phreatic water bodies of caves located within two separated metasedimentary basins in the region of Chapada Diamantina, Bahia state, Brazil. In order to test the hypothesis of isolation with differentiation of the groups from the Una‐Utinga and Irecê metasedimentary basins, we compared five populations among themselves and with an epigean species of Rhamdiopsis. This was accomplished using geometric morphometrics, a powerful tool for detecting differences in body shape at population and species levels. All studied samples differed significantly from each other, the epigean sample being the most distinct and the Una Basin populations clustering together. Geological and hydrological barriers explain the differences among the subterranean populations. We discuss our results together with the autapomorphies found in R. krugi, which validate its monophyly. These results imply an old age for the R. krugi clade, more than 10 Myr; alternative hypotheses are also presented. We propose a two‐step vertical colonization model of the subterranean habitat through the hyporheic zone by an epigean ancestral, with a progressive acquisition of the autapomorphies characterizing R. krugi. For conservation purposes, the two differentiated sets of populations should be considered and referred to as R. krugi ‘Una morphotype’ and R. krugi ‘Irecê morphotype’. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 114 , 136–151. 相似文献
69.
Mark Manzano Eleonora Forte Archana N. Raja Matthew J. Schipma Eva Gottwein 《RNA (New York, N.Y.)》2015,21(9):1606-1620
Sequence heterogeneity at the ends of mature microRNAs (miRNAs) is well documented, but its effects on miRNA function are largely unexplored. Here we studied the impact of miRNA 5′-heterogeneity, which affects the seed region critical for target recognition. Using the example of miR-142-3p, an emerging regulator of the hematopoietic lineage in vertebrates, we show that naturally coexpressed 5′-variants (5′-isomiRs) can recognize largely distinct sets of binding sites. Despite this, both miR-142-3p isomiRs regulate exclusive and shared targets involved in actin dynamics. Thus, 5′-heterogeneity can substantially broaden and enhance regulation of one pathway. Other 5′-isomiRs, in contrast, recognize largely overlapping sets of binding sites. This is exemplified by two herpesviral 5′-isomiRs that selectively mimic one of the miR-142-3p 5′-isomiRs. We hypothesize that other cellular and viral 5′-isomiRs can similarly be grouped into those with divergent or convergent target repertoires, based on 5′-sequence features. Taken together, our results provide a detailed characterization of target recognition by miR-142-3p and its 5′-isomiR-specific viral mimic. We furthermore demonstrate that miRNA 5′-end variation leads to differential targeting and can thus broaden the target range of miRNAs. 相似文献
70.
Roel Hermsen Joep de Ligt Wim Spee Francis Blokzijl Sebastian Sch?fer Eleonora Adami Sander Boymans Stephen Flink Ruben van Boxtel Robin H van der Weide Tim Aitman Norbert Hübner Marieke Simonis Boris Tabakoff Victor Guryev Edwin Cuppen 《BMC genomics》2015,16(1)