Receptor-mediated endocytosi

They encapsulated poly(MA-CDA) into mannan-coated liposomes and evaluated superoxide production from mouse macrophages. The activity was three- to five-fold high compared with uncapsulated poly(MA-CDA) itself [5,11], suggesting that an increased incorporation of the polymer by the receptor-mediated endocytosis mediated the higher biological activity.. 

A process in which a substance gains entry into a cell. Endocytic mechanisms are crucial for a variety of cellular functions such as the uptake of nutrients, regulation of cell surface expression of receptors, maintenance of cell polarity, and more. Receptor-mediated endocytosis via clathrin-coated pits is the most studied endocytic process, which is important for regulation of the time and magnitude of signals generated by a variety of cell-surface receptors. 

Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by a receptor specific for apo E (Figure 25-3), and both the LDL (apo B-lOO, E) receptor and the LRP (LDL receptor-related protein)... 

Figure 41 -15. Two types of endocytosis. An endocytotic vesicle (V) forms as a result of invagination of a portion of the plasma membrane. Fluid-phase endocytosis (A) is random and nondirected. Receptor-mediated endocytosis (B) is selective and occurs in coated pits (CP) lined with the protein clathrin (the fuzzy material). Targeting is provided by receptors (black symbols) specific for a variety of molecules. This results in the formation of a coated vesicle (CV).

There are receptors (TfRs) on the surfaces of many cells for transferrin, it binds to these receptors and is internalized by receptor-mediated endocytosis (compare the fate of LDL Chapter 25). The acid pH inside the lysosome causes the iron to dissociate from the protein. The dissociated iron leaves the endosome via DMTl to enter the cytoplasm. Unlike the protein component of LDL, apoTf is not degraded within the lysosome. Instead, it remains associated with its receptor, returns to the plasma membrane, dissociates from its receptor, reenters the plasma, picks up more iron, and again delivers the iron to needy ceils. 

Lee, R. J. Wang, S. Low, R S., Measurement of endosome pH following folate receptor-mediated endocytosis, Biochim. Biophys. Acta 1312, 237-242 (1996). 

RJ Fallon, AL Schwartz. Receptor-mediated endocytosis and targeted drug delivery. Hepatology 5 899-901, 1985. 

Transferrin iron uptake via receptor-mediated endocytosis has clearly appeared fairly late in evolution, when we consider that the bilobal iron-binding protein is found only as far back as insects . As we have seen in the preceding chapters, iron-uptake mechanisms involving the synthesis of more or less specific siderophores have evolved together with strategies implying the solubilization of insoluble ferric iron by the combined effects of pH and reduction, and even the development of receptor proteins capable of taking up transferrin-, lactoferrin- or haem-bound iron from specific hosts. 

Figure 11.1 Schematic representation of iron uptake mechanisms, (a) The transferrin-mediated pathway in animals involves receptor-mediated endocytosis of diferric transferrin (Tf), release of iron at the lower pH of the endocytic vesicle and recycling of apoTf. (b) The mechanism in H. influenzae involves extraction of iron from Tf at outer membrane receptors and transport to the inner membrane permease system by a periplasmic ferric binding protein (Fbp). From Baker, 1997. Reproduced by permission of Nature Publishing Group.

The abundant expression of a variety of transporters in Caco-2 cells also makes it attractive to apply functional genomics tools, such as cDNA arrays in order to map the expression [31] and relative abundance of these transporters [32], Also, genomic mapping of surface receptors on Caco-2 cells can be performed to study receptor-mediated endocytosis and other endocytotic pathways for larger molecules in enterocytes [33-36]. 

The oral administration of large proteins and peptides is limited due to their low membrane permeability. These compounds are mainly restricted to the para-cellular pathway, but because of their polar characteristics and their size the pore of the tight junctional system is also highly restrictive. An additional transcellular pathway has therefore been suggested for these peptides, i.e., the transcytotic pathway, which involves a receptor-mediated endocytosis in Caco-2 cells [126],... 

Yang, J, Chen, H, Vlahov, I. R, Cheng, J. X. and Low, P. S. (2006a). Evaluation of disulfide reduction during receptor-mediated endocytosis by using FRET imaging. Proc. Natl. Acad. Sci. USA 103, 13872-13877. 

W. W. Liang, X. Shi, D. Deshpande, C. J. Malanga, and Y. Rojanasakul, Oligonucleotide targeting to alveolar macrophages by mannose receptor-mediated endocytosis, Biochim. Biophys. Acta, 1279 (1996) 227-234. 

Wagner E, Curiel D, Cotten M (1994) Delivery of drugs, proteins and genes into cells using transferrin as a ligand for receptor-mediated endocytosis. Adv Drug Del Rev 14 113-136... 

Zenke M, Steinlein P, Wagner E, Cotten M, Beug H, Bimstiel ML (1990) Receptor-mediated endocytosis of transferrin-polycation conjugates an efficient way to introduce DNA into hematopoietic cells. Proc Natl Acad Sci USA 87 3655-3659... 

Curiel DT, Agarwal S, Romer N, Wagner E, Cotten M, Bimstiel ML, Boucher RC (1992) Gene transfer to respiratory epithelial cells via the receptor-mediated endocytosis pathway. Am J Resp Cell Mol Biol 6 247-252... 

Chen J, Gamou S, Takayanagi A, Shimizu N (1994) A novel gene delivery system using EGF receptor-mediated endocytosis 97. FEBS Lett 338 167-169... 

Michael SI, Huang CH, Romer MU, Wagner E, Hu PC, Curiel DT (1993) Binding-incompetent adenovirus facilitates molecular conjugate-mediated gene transfer by the receptor-mediated endocytosis pathway. J Biol Chem 268 6866-6869... 

Keen, J.H., Maxfield, F.R., Hardegree, M.C., and Habig, W.H. (1982) Receptor-mediated endocytosis of diphtheria toxin by cell in culture. Proc. Natl Acad. Sci. USA 79, 2912. 

Some attempts have been made to rationally increase the efficiency of endosomal escape. One such avenue entails the incorporation of selected hydrophobic (viral) peptides into the gene delivery systems. Many viruses naturally enter animal cells via receptor-mediated endocytosis. These viruses have evolved efficient means of endosomal escape, usually relying upon membrane-disrupting peptides derived from the viral coat proteins. 

The precise mechanism(s) by which oligos enter cells is not fully understood. Most are charged molecules, sometimes displaying a molecular mass of up to 10-12 kDa. Receptor-mediated endocytosis appears to be the most common mechanism by which charged oligos, such as phosphorothioates, enter most cells. One putative phosphorothioate receptor appears to consist of an 80 kDa surface protein, associated with a smaller 34 kDa membrane protein. However, this in itself seems to be an inefficient process, with only a small proportion of the administered drug eventually being transferred across the plasma membrane. 

Lipids are transported between membranes. As indicated above, lipids are often biosynthesized in one intracellular membrane and must be transported to other intracellular compartments for membrane biogenesis. Because lipids are insoluble in water, special mechanisms must exist for the inter- and intracellular transport of membrane lipids. Vesicular trafficking, cytoplasmic transfer-exchange proteins and direct transfer across membrane contacts can transport lipids from one membrane to another. The best understood of such mechanisms is vesicular transport, wherein the lipid molecules are sorted into membrane vesicles that bud out from the donor membrane and travel to and then fuse with the recipient membrane. The well characterized transport of plasma cholesterol into cells via receptor-mediated endocytosis is a useful model of this type of lipid transport. [9, 20]. A brain specific transporter for cholesterol has been identified (see Chapter 5). It is believed that transport of cholesterol from the endoplasmic reticulum to other membranes and of glycolipids from the Golgi bodies to the plasma membrane is mediated by similar mechanisms. The transport of phosphoglycerides is less clearly understood. Recent evidence suggests that net phospholipid movement between subcellular membranes may occur via specialized zones of apposition, as characterized for transfer of PtdSer between mitochondria and the endoplasmic reticulum [21]. 

Retrieval of membrane components in the secretory pathway through receptor-mediated endocytosis (RME) isaclathrin-coat-dependent process 155... 

Under some circumstances, lysosomal hydrolases may fail to be properly packaged in the TGN, so they enter the default pathway to the cell surface, where they are secreted. Although these hydrolases do little harm at the nearly neutral pH of most extracellular fluids, they can also be returned to lysosomes by a pathway known as receptor-mediated endocytosis. In this pathway, M6P receptors are sent to the plasma membrane, where they bind escaped lysosomal hydrolases and bring them back to lysosomes through the early and late endosomes. Receptor-mediated endocytosis is a major component of the endocytic pathways for trafficking of membrane proteins and merit more detailed consideration. 

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