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461.
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Sharon Eisenberg Ehud Haimov Glenn F. W. Walpole Jonathan Plumb Michael M. Kozlov Sergio Grinstein 《Molecular biology of the cell》2021,32(3):301
Anionic phospholipids can confer a net negative charge on biological membranes. This surface charge generates an electric field that serves to recruit extrinsic cationic proteins, can alter the disposition of transmembrane proteins and causes the local accumulation of soluble counterions, altering the local pH and the concentration of physiologically important ions such as calcium. Because the phospholipid compositions of the different organellar membranes vary, their surface charges are similarly expected to diverge. Yet, despite the important functional implications, remarkably little is known about the electrostatic properties of the individual organellar membranes. We therefore designed and implemented approaches to estimate the surface charges of the cytosolic membranes of various organelles in situ in intact cells. Our data indicate that the inner leaflet of the plasma membrane is most negative, with a surface potential of approximately –35 mV, followed by the Golgi complex > lysosomes > mitochondria ≈ peroxisomes > endoplasmic reticulum, in decreasing order.Lipids and (glyco)proteins are the main constituents of biological membranes. Sugar moieties of glycoproteins, glycolipids, and adherent glycocalyx components such as hyaluronic acid can bear ionizable groups that confer a net negative charge on the outer surface of the plasma membrane. The aggregate surface charge of the outer membrane has been estimated indirectly by measuring the ζ potential—the potential at the slipping plane—by electrophoretic means (e.g., Tippe, 1981; Silva Filho et al., 1987) or by measuring streaming potentials (Vandrangi et al., 2012). The plasma membrane, however, is highly asymmetric; its inner (cytosolic) aspect is virtually devoid of carbohydrate moieties. Nevertheless, the cytosolic leaflet is also thought to be negatively charged, due primarily to the accumulation of anionic phospholipids, namely phosphoinositides and phosphatidylserine (PtdSer). Based on biochemical determinations of its lipid composition, the net negative charge of the plasmalemmal inner leaflet is estimated to generate an electrical field of 105 V/cm (Olivotto et al., 1996). The membranes of intracellular organelles can also contain anionic lipids, but their precise lipid composition and topology have been difficult to assess and hence their surface charge has not been estimated.The surface potentials of biological membranes have important functional implications: they can alter the disposition of charged regions of transmembrane proteins, cause local accumulation of soluble counterions in the vicinity—altering the local pH as well as the concentration of physiologically important ions such as calcium—and serve to recruit extrinsic cationic proteins (McLaughlin, 1989). It is therefore important to determine the electrostatic properties of each of the organellar membranes. In principle, this could be accomplished by measuring the ζ potentials of isolated organelles. However, the purity of such preparations is imperfect, changes in lipid composition (particularly phosphoinositide degradation) and sidedness cannot be avoided, and loosely adherent components that may alter the surface charge can be removed during the isolation process. Alternative approaches to estimating the surface potential are therefore required.Here we used recombinant and synthetic polycationic peptides to obtain a quantitative estimate of the surface potential of the inner leaflet of the plasma membrane and to establish a hierarchical map of the potentials of the cytosolic surfaces of the major intracellular organelles in live cells. 相似文献
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In an attempt to synthesize compounds with selective estrogen-receptor binding, fluoro- and amino-clomiphene were totally synthesized from benzyl chloride, and their estrogenic/antiestrogenic activity as well as that of some of their chemical intermediates was evaluated. The triazene prepared from the amino-clomiphene was converted into fluoro-clomiphene with 39% yield. In the uterotropic test, both amino- and fluoro-clomiphene exerted mild equipotent estrogenic activity, with minimal saturation doses being 50 and 100 micrograms/rat/day for three days. In the receptor binding test both derivatives demonstrated similar displacement, with an A50% value in the 10(-5) M range, as compared to 10(-6) M for clomiphene and 10(-9) M for diethyl-stilbestrol. This synthesis may be useful for the preparation of 18F-labeled clomiphene for biodistribution studies. 相似文献
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Tyrphostins inhibit the epidermal growth factor receptor-mediated breakdown of phosphoinositides 总被引:3,自引:0,他引:3
In response to epidermal growth factor (EGF) and the Ca2+ ionophore A23187, the total phosphatidylinositides (IPT) increased in A431 human epidermoid carcinoma cells 1.8- and 2.0-fold and in the EGF-dependent A431/Clone 15-2 cells 3.0- and 8.0-fold, respectively, over basal levels. Both responses were inhibited by the antiproliferative agents tyrphostins, but the EGF-induced increase in IPT was inhibited to a much greater extent than that induced by the ionophore. Tyrphostins which are potent EGF-receptor kinase inhibitors were also potent in blocking the EGF-induced production of phosphoinositides. The less potent tyrphostins were found to inhibit the EGF-dependent IPT formation more weakly. These results support the notion that phospholipase C is activated through its phosphorylation by the EGF receptor. 相似文献