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21.
Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor. 总被引:6,自引:1,他引:5 下载免费PDF全文
E F Grady A M Garland P D Gamp M Lovett D G Payan N W Bunnett 《Molecular biology of the cell》1995,6(5):509-524
Many of the actions of the neuropeptide substance P (SP) that are mediated by the neurokinin 1 receptor (NK1-R) desensitize and resensitize, which may be associated with NK1-R endocytosis and recycling. We delineated this endocytic pathway in transfected cells by confocal microscopy using cyanine 3-SP and NK1-R antibodies. SP and the NK1-R were internalized into the same clathrin immunoreactive vesicles, and then sorted into different compartments. The NK1-R was colocalized with a marker of early endosomes, but not with markers of late endosomes or lysosomes. We quantified the NK1-R at the cell surface by incubating cells with an antibody to an extracellular epitope. After exposure to SP, there was a loss and subsequent recovery of surface NK1-R. The loss was prevented by hypertonic sucrose and potassium depletion, inhibitors of clathrin-mediated endocytosis. Recovery was independent of new protein synthesis because it was unaffected by cycloheximide. Recovery required endosomal acidification because it was prevented by an H(+)-ATPase inhibitor. The fate of internalized 125I-SP was examined by chromatography. SP was intact at the cell surface and in early endosomes, but slowly degraded in perinuclear vesicles. We conclude that SP induces clathrin-dependent internalization of the NK1-R. The SP/NK1-R complex dissociates in acidified endosomes. SP is degraded, whereas the NK1-R recycles to the cell surface. 相似文献
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The conformational transition between the α- and 310-helical states of α-methylalanine homopeptides is studied with molecular mechanics. Conformational transition pathways for Ace-(MeA)n-NMe with n = 7, 9, and 11 are obtained with the algorithms of Elber and co-workers [R. Czerminski & R. Elber (1990) International Journal of Quantum Chemistry, Vol. 24, pp. 167–186; A. Ulitsky & R. Elber (1990) Journal of Chemical Physics, Vol. 92, pp. 1510–1511]. The free energy surface, or potential of mean force, for the conformational transition of Ace-(MeA)9-NMe is calculated from molecular dynamics simulations, and a method is presented for the decomposition of the free energy surface into the constituent energetic and entropic terms, via the calculation of the required temperature derivatives in situ. For the AMBER/OPLS model employed here, the conformational transition pathways each contain a single 310-helical-like transition state, and the transition state potential energy relative to the 310-conformation is 3 kcal/mol, independent of peptide length. Entropic stabilization in the barrier region significantly lowers the activation free energies for the forward and reverse transitions from the estimates of the barrier heights based simply on potential energy alone. © 1994 John Wiley & Sons, Inc. 相似文献
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Denise D. Beusen Janusz Zabrocki Urszula Slomczynska Richard D. Head Jeff L.-F. Kao Garland R. Marshall 《Biopolymers》1995,36(2):181-200
Potent, cyclic hexapeptide analogues of somatostatin are generally believed to adopt some common secondary structural features: a II′ β turn at one end of the cycle, and a type VI turn with a cis amide bond at the other. A proposed cis amide surrogate, the 1,5-disubstituted tetrazole, has been placed into a cyclic hexapeptide analog of somatostatin in order to constrain the putative cis amide bond. The final cyclization was done by either chemical or enzymatic means. The product, cyclo(Ala6-Tyr7-D -Trp8-Lys9-Val10-Phe11-Ψ[CN4]), was found to have 83% of the activity of somatostatin. Solution nmr analysis in DMSO/water revealed that the backbone as well as side chain χ1 and χ2 were well ordered. Relaxation matrix methods were used to extract distance restraints from the nuclear Overhauser effect spectroscopy data set, and these were used in a systematic search of torsional space to identify structures consistent with the nmr data. Restrained minimizations of these structures using a number of different force fields produced structures having the expected βII′ turn at D -Trp8-Lys9 and αβVIa turn in the Phe11-Ψ[CN4]-Ala6 portion of the molecule. The similarity of the minimized structures to those previously reported for cyclic hexapeptide analogues of somatostatin confirms the similarity of the tetrazole geometry to that of the cis amide in solution. © 1995 John Wiley & Sons, Inc. 相似文献
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High affinity epidermal growth factor receptors on the surface of A431 cells have restricted lateral diffusion 总被引:11,自引:3,他引:8 下载免费PDF全文
Rhodamine-labelled epidermal growth factor (Rh-EGF) was shown to bind to A431 cells grown at low density both to a small number of high affinity receptors (KD = 2.8 X 10(-10) M; fraction of total binding sites approximately 0.12) and also to a large number of low affinity receptors (KD = 4 X 10(-9) M; fraction of total binding sites approximately 0.88). Measurements of the lateral diffusion of EGF receptors on the cell surface were made using Rh-EGF and the technique of fluorescence photobleaching recovery. The high affinity receptors (labelled with 1.6 X 10(-10) M Rh-EGF, 5% of EGF binding sites occupied) did not show lateral mobility over the temperature range 3 degrees-37 degrees C. The low affinity receptors (labelled with 2.4 X 10(-7) M Rh-EGF, 90% of EGF sites occupied) showed at least 75% fluorescence recovery after photobleaching, and lateral diffusion coefficients of approximately 2 X 10(-10) cm2/s. These results show that the two populations of EGF receptors defined by binding studies differ in their freedom to diffuse laterally. The observation that the high affinity receptors are immobile indicates that lateral diffusion of receptors, at least over a distance of a few hundred nanometres or more, may not be required for the action of low concentrations of EGF. 相似文献
27.
J.J. Adcock L.G. Garland S. Moncada J.A. Salmon 《Prostaglandins & other lipid mediators》1978,16(2):163-177
Fragments of chopped lung from indomethacin treated guinea-pigs had an anti-aggregating effect when added to human platelet rich plasma (PRP), probably due to the production of prostacyclin (PGI2) since the effect was inhibited by 15-hydroperoxy arachidonic acid (15-HPAA, 10 μg ml?1). Both 15-HPAA (1–20 μg ml?1 min?1) and 13-hydroperoxy linoleic acid (13-HPLA, 20 μg ml?1 min?1) caused a marked enhancement of the anaphylactic release of histamine, slow-reacting substance of anaphylaxis (SRS-A) and rabbit aorta contracting substance (RCS) from guinea-pig isolated perfused lungs. This enhancement was not reversed by the concomitant infusion of either PGI2 (5 μg ml?1 min?1) or 6-oxo-prostaglandin F1α (6-oxo-PGF1α, 5 μg ml?1 min?1). Anaphylactic release of histamine and SRS-A from guinea-pig perfused lungs was not inhibited by PGI2 (10 ng - 10 μg ml?1 min?1) but was inhibited by PGE2 (5 and 10 μg ml?1 min?1). Antiserum raised to 5,6-dihydro prostacyclin (PGI1) in rabbits, which also binds PGI2, had no effect on the release of anaphylactic mediators. The fatty acid hydroperoxides may enhance mediator release either indirectly by augmenting thromboxane production or by a direct effect on sensitized cells. Further experiments to distinguish between these alternatives are described in the accompanying paper (27). 相似文献
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Indomethacin augmented the release of histamine and SRS-A but abolished synthesis of TxB2. Compound CLI that inhibited both cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism did not augment release of anaphylactic mediators. 13-HPLA enhanced mediator release from lungs in which arachidonic acid metabolism was blocked by compount CLI. Thus, it is concluded that 13-HPLA enhances mediator release not by altering the balance of arachidonic acid metabolites, e.g. by inhibiting synthesis of prostacyclin, but by a direct effect on lung mast cells. A corollary to this conclusion is that the fatty acid hydroperoxide (HPETE) formed by lipoxygenase from arachidonic acid may also augment the release of anaphylactic mediators. Thus, the enhancement of mediator release by indomethacin may be attributed to increased synthesis of HPETE following inhibition of cyclo-oxygenase. 相似文献
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F. Rubio F. de Grazia B.J. Miwa W.A. Garland 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1982,233(1):149-155
A method is described for measuring (-)-threo-chlorocitric acid in human plasma. Plasma is acidified to pH 1 to minimize lactonization and a13C analogue of (-)-threo-chlorocitric acid is added as internal standard. The acidified plasma is then extracted with ethyl acetate containing 10% methanol. The ethyl acetate—methanol extract is back-extracted with acetate buffer (pH 5). This extract, following adjustment to pH 1, is reextracted with ethyl acetate. The residue after removal of the ethyl acetate is treated with ethereal diazomethane. The wet residue is reconstituted in ethyl acetate and a portion of this solution is analyzed by gas chromatography—chemical ionization mass spectrometry. The mass spectrometer is set to monitorm/z269 [MH+ of trimethylated (-)-threo-chlorocitric acid] andm/z270 [MH+ of trimethylated (-)-threo-[13C]chlorocitric acid] in the gas chromatographic effluent. Them/z/269 tom/z270 ion ratio in a sample containing an unknown amount of (-)-threo-chlorocitric acid is converted to an amount of compound using a calibration curve. The calibration curve is generated by analyzing control plasma spiked with various known amounts of (-)-threo-chlorocitric acid and a fixed amount of (-)-threo-[13C]chlorocitric acid. The limit of quantitation is 0.1–0.6 μg ml−1, depending on the characteristics of the calibration curve generated with each set of samples. The precision (relative standard deviation) at a concentration of 2 μg ml−1 is 3.3%. 相似文献