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241.
Zhang W Zitron E Hömme M Kihm L Morath C Scherer D Hegge S Thomas D Schmitt CP Zeier M Katus H Karle C Schwenger V 《The Journal of biological chemistry》2007,282(29):20933-20940
Aquaporin-1 (AQP1) channels contribute to osmotically induced water transport in several organs including the kidney and serosal membranes such as the peritoneum and the pleura. In addition, AQP1 channels have been shown to conduct cationic currents upon stimulation by cyclic nucleotides. To date, the short term regulation of AQP1 function by other major intracellular signaling pathways has not been studied. In the present study, we therefore investigated the regulation of AQP1 by protein kinase C. AQP1 wild type channels were expressed in Xenopus oocytes. Water permeability was assessed by hypotonic challenges. Activation of protein kinase C (PKC) by 1-oleoyl-2-acetyl-sn-glycerol (OAG) induced a marked increase of AQP1-dependent water permeability. This regulation was abolished in mutated AQP1 channels lacking both consensus PKC phosphorylation sites Thr(157) and Thr(239) (termed AQP1 DeltaPKC). AQP1 cationic currents measured with double-electrode voltage clamp were markedly increased after pharmacological activation of PKC by either OAG or phorbol 12-myristate 13-acetate. Deletion of either Thr(157) or Thr(239) caused a marked attenuation of PKC-dependent current increases, and deletion of both phosphorylation sites in AQP1 DeltaPKC channels abolished the effect. In vitro phosphorylation studies with synthesized peptides corresponding to amino acids 154-168 and 236-250 revealed that both Thr(157) and Thr(239) are phosphorylated by PKC. Upon stimulation by cyclic nucleotides, AQP1 wild type currents exhibited a strong activation. This regulation was not affected after deletion of PKC phosphorylation sites in AQP1 DeltaPKC channels. In conclusion, this is the first study to show that PKC positively regulates both water permeability and ionic conductance of AQP1 channels. This new pathway of AQP1 regulation is independent of the previously described cyclic nucleotide pathway and may contribute to the PKC stimulation of AQP1-modulated processes such as endothelial permeability, angiogenesis, and urine concentration. 相似文献
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Ferrão-Gonzales AD Robbs BK Moreau VH Ferreira A Juliano L Valente AP Almeida FC Silva JL Foguel D 《The Journal of biological chemistry》2005,280(41):34747-34754
Aggregation of proteins and peptides has been shown to be responsible for several diseases known as amyloidoses, which include Alzheimer disease (AD), prion diseases, among several others. AD is a neurodegenerative disorder caused primarily by the aggregation of beta-amyloid peptide (Abeta). Here we describe the stabilization of small oligomers of Abeta by the use of sulfonated hydrophobic molecules such as AMNS (1-amino-5-naphthalene sulfonate); 1,8-ANS (1-anilinonaphthalene-8-sulfonate) and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonate). The experiments were performed with either Abeta-1-42 or with Abeta-13-23, a shorter version of Abeta that is still able to form amyloid fibrils in vitro and contains amino acid residues 16-20, previously shown to be essential to peptide-peptide interaction and fibril formation. All sulfonated molecules tested were able to prevent Abeta aggregation in a concentration dependent fashion in the following order of efficacy: 1,8-ANS < AMNS < bis-ANS. Size exclusion chromatography revealed that in the presence of bis-ANS, Abeta forms a heterogeneous population of low molecular weight species that proved to be toxic to cell cultures. Since the ANS compounds all have apolar rings and negative charges (sulfonate groups), both hydrophobic and electrostatic interactions may contribute to interpeptide contacts that lead to aggregation. We also performed NMR experiments to investigate the structure of Abeta-13-23 in SDS micelles and found features of an alpha-helix from Lys(16) to Phe(20). 1H TOCSY spectra of Abeta-13-23 in the presence of AMNS displayed a chemical-shift dispersion quite similar to that observed in SDS, which suggests that in the presence of AMNS this peptide might adopt a conformation similar to that reported in the presence of SDS. Taken together, our studies provide evidence for the crucial role of small oligomers and their stabilization by sulfonate hydrophobic compounds. 相似文献
244.
Mu-calpain is functionally required for alpha-processing of Alzheimer's beta-amyloid precursor protein 总被引:2,自引:0,他引:2
Alzheimer's beta-amyloid precursor protein (APP) is normally processed by an unidentified alpha-secretase. A unique feature of this protease is its high sensitivity to phorbol esters, yet the mechanism involved is unclear. We have previously reported that phorbol 12,13-dibutyrate (PDBu) activates calpain, a Ca2+-dependent protease, and PDBu-induced release of APPs (secreted APP) is sensitive to calpain inhibitors, suggesting that calpain is involved in APP alpha-processing. In the present study, we found that PDBu markedly promoted the expression of both mu- and m-calpains in cultured fibroblasts. Dose-response and time course studies revealed that mu-calpain was more sensitive to PDBu than m-calpain and the temporal course of the mu-calpain change coincides better with that of APPs release. Moreover, the stimulatory effect of PDBu on mu-calpain was selectively blocked by mu-calpain-specific siRNA (small interference RNA) and the blockage was accompanied by a concomitant decrease in APPs release. In contrast, m-calpain siRNA did not affect APPs release significantly. Measurement of amyloid beta protein (Abeta) release in the mu-calpain siRNA-treated cells indicated that Abeta40 and Abeta42 levels inversely changed in relation to APPs, and the changes in Abeta42 were more prominent than in Abeta40. Together, these data suggest that calpain, particularly mu-calpain, is a potential candidate for alpha-secretase in the regulated APP alpha-processing, and that changes in this protease can affect the outcome of the overall APP processing. 相似文献
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Côrte-Real R Gomes RN Castro-Faria-Neto HC Azambuja P Garcia ES 《Journal of insect physiology》2011,57(6):825-829
In this work, we investigated the activity of the platelet activating factor acetyl hydrolase (PAF-AH) in the salivary gland homogenates and saliva of Rhodnius prolixus. PAF-AH activity in the salivary gland homogenates was lower than in the saliva. Preliminary characterization of the enzyme demonstrated that it hydrolyzed the substrate 2-thio-PAF, was detectable just in 1 pair of salivary gland homogenates in 0.5 ml buffer, and was stable under different conditions. PMSF, TPCK, TLCK, pepstatin A and p-BPB all inhibited the PAF-AH activity. Enzyme specific activity in salivary gland homogenates diminished immediately after feeding of 5th-instar larvae, and increased before feeding by adult insects. 2-Thio-PAF induced platelet-aggregation that was inhibited by previous incubation of the substrate with salivary gland homogenates or saliva. The relevance of PAF-AH for providing Rhodnius with a feeding mechanism for facilitating the sucking of a high volume of blood meal in a short period is discussed. 相似文献
249.
Javier GiglioSoledad Fernández Ana Rey Hugo Cerecetto 《Bioorganic & medicinal chemistry letters》2011,21(1):394-397
With the aim to develop new potential 99mTc-radiopharmaceuticals for imaging hypoxia based on the formation of Tc-nitrido complexes, two novel dithiocarbamate containing metronidazole derivatives (L1 and L2) have been prepared and characterised. The synthesis of L1 and L2 was achieved in excellent yield and high purity. Labelling with 99mTc was successfully performed using a low ligand concentration (approximately 2-3 mg) and the desired products were obtained with high radiochemical purity (>90%). Lipophilicity, plasma protein binding, and biodistribution in normal- and tumour-bearing-CD1 mice studies were performed to asses the potentiality for nuclear medicine oncology. According to the physicochemical and biological behaviour both in healthy animals and in animals bearing solid tumours complex dtcTc1 could be considered as a starting point for the development of new radiopharmaceuticals for imaging hypoxia. 相似文献
250.
Ricardo?S.?CeiaEmail author Hugo?L.?Sampaio Sandra?H.?Parejo Ruben?H.?Heleno Maria?L.?Arosa Jaime?A.?Ramos Geoff?M.?Hilton 《Biological invasions》2011,13(1):93-104
The invasive Clethra arborea has a dual-role in the diet of the Azores bullfinch, a critically endangered bird species endemic to the island of São Miguel (Azores, Portugal). This is a crucial winter food resource but it lowers the availability of native laurel forest species that compose most of the bird’s diet throughout the year. The removal of this and other invasive alien species is part of current laurel forest habitat restoration programmes, disregarding the impact on the Azores bullfinch population. In order to evaluate the first responses of the Azores bullfinch to habitat restoration, we studied bird diet, foraging behaviour, food availability and habitat occupancy in managed (without C. arborea) and control areas. Significant increases in the availability of native food resources in managed areas were noticeable in the diet, particularly the intake of Ilex perado ssp. azorica and Prunus lusitanica ssp. azorica flower buds. In most of the studied months birds heavily used and foraged in managed over control areas. The one exception was in December, when a resource-gap occurred in managed areas, which may be overcome in the short-term due to re-establishment of native plants following removal of invasive aliens. 相似文献