Receptor-mediated endocytosis, and

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)... 

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

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 bulk of pinocytosis in the nervous system is mediated by clathrin-mediated endocytosis (CME) [55] and this is the best-characterized pathway. More detail about clathrin-mediated pathways will be given when receptor-mediated endocytosis and the synaptic vesicle cycle pathways are considered. Pinocytosis through CME is responsible for uptake of essential nutrients such as cholesterol bound to low density lipoprotein (LDL) and transferring, but also plays a role in regulating the levels of membrane pumps and channels in neurons. Finally, CME is critical for normal synaptic vesicle recycling. 

Possible explanations for a blood flow-limited uptake in kidney include the existence of specific uptake mechanisms, such as receptor-mediated endocytosis and carrier-mediated transport. Since the former mechanism is initiated by binding of the ligand to the cell-surface receptor, the specific binding of alkylglycoside compounds to isolated tubular plasma membranes was examined [23,24]. 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

Goldstein, J.L., R.G. Anderson, and M.S. Brown. 1982. Receptor-mediated endocytosis and the cellular uptake of low density lipoprotein. Ciba Found Symp 11. 

Physical barrier. Following oral administration of macromolecular drugs, their potential absorption pathways from the intestinal lumen to the bloodstream can be classified into transcellular transport associated with adsorptive or receptor-mediated endocytosis and paracellu-lar transport (Fig. 10.1). The GI tract surface consists of a tightly bound single layer of epithelial cells covered with thick and viscous mucus, which serves as a defensive deterrent against permeation of xenobi-otics and harmful pathogens. The epithelial cells in the GI tract are... 

Numerous studies have pointed to an important role for cholesterol during proliferation and progression of cancer (e.g., ref. 612-615). Rapidly dividing cancer cells have two major routes to fulfill their need for cholesterol to form new cell membrane endogenous synthesis of cholesterol and/or receptor-mediated uptake of exogenous LDL particle-associated cholesterol and cholesterol esters (ref. 612,613,615). Each LDL particle contains a cholesterol ester core surrounded by a polar shell of phospholipids (primarily phosphoglycerides), free cholesterol, and apolipoprotein B (ref. 616-618). Once bound to its cell surface receptor, LDL is internalized by receptor-mediated endocytosis and degraded in lysosomes, and the subsequently released cholesterol may be used for membrane synthesis by the tumor (ref. 619). 

HDLs are synthesized in the blood and extract cholesterol from cell membranes, converting it into cholesterol esters. Some of the cholesterol esters are then transferred to VLDLs. About half of the VLDLs and all of the HDLs are taken up into the liver cells by receptor-mediated endocytosis and the cholesterol disposed of in the form of bile salts. 

Fig. 2. Aluminum uptake by receptor-mediated endocytosis and transferrin-independent iron uptake systems in mammalian cells...

Three processes are involved in transcellular transport across the intestinal epithelial cells simple passive trans-port, passive diffusion together with an efflux pump, and active transport and endocytosis. Simple passive transport is the diffusion of molecules across the membrane by thermodynamic driving forces and does not require direct expenditure of metabolic energy. In contrast, active transport is the movement of molecules across the mem-brane resulting directly from the expenditure of metabolic energy and transport against a concentration gradient. Endocytosis processes include three mechanisms fluid-phase endocytosis (pinocytosis), receptor-mediated endocytosis, and transcytosis (Fig. 6). Endocytosis processes are covered in detail in section Absorption of Polypeptides and Proteins, later. 

Fig. 6 Schematic depiction of cellular uptake mechanisms fluid-phase endocytosis, receptor-mediated endocytosis, and transc5dosis. (Illustration by Leigh A. Rondano, Boehringer Ingelheim Pharmaceuticals, Inc.)...

After the initial binding to the anionic phospholipids of the PTC, the aminoglycoside molecule is quickly transferred to the transmembrane protein megalin and endocytosed [42, 43, 48-50, 52-59, 66-68, 72, 73]. Aminoglycosides enter the PTC on either the apical or basolateral plasma membrane via receptor-mediated endocytosis. and are ultimately sequestered in the same endosomal compartment [68]. In an experiment with LLC-PKl cells. Ford et al. demonstrated that aminoglycosides were internalized equally across the apical and basolateral membranes by receptor-mediated endocytosis. This was followed by colocalization within the lysosomal compartment and similar magnitudes of cellular dysfunction [68]. 

Figure 1 Parallel pathways of intestinal absorption (1) paracellular pathway, (2) trans-cellular pathway, (2a) carrier-mediated, (2b) passive diffusion, (2c) receptor-mediated endocytosis, and (3) mediated efflux pathway. (From Ref. 30.)...

Fig-1 The final NM-induced toxic effect observed in vitro is the result of multiple processes (1) interaction with proteins (formation of the protein corona, activation/inactivation of enzymes) (2) dissolution and release of toxic ions (3) production of ROS at the NMs surface (4) aggregation/agglomeration (5) diffusion and sedimentation that influence NM transport to the cell layer and the final effective concentration (6) interaction with the cell membrane and membrane receptors (activation/inhibition) (7) cell uptake (including receptor-mediated endocytosis and other uptake mechanisms) (8) interaction with intracellular enzymes (activation/inhibition) (9) production of intracellular ROS (10) activation of transcription factors and (11) binding to nucleic acids and genotoxicity, among others. Processes (1)—(5) are closely interconnected. The resulting effect observed is the result of the composite rate of all these different reactions... 

Figure 8,1, Routes and mechanisms of solute transport across epithelial membranes. In general, routes 2-5 are transcellular pathways (i.e., compounds move through the cells), whereas route 1 is considered a paracellular pathway (i.e., a compound moves between the cells). (l)Tight junctional pathway (2) drug efflux pathway (e.g., P-glycoprotein mediated) (3) passive diffiision (4)receptor-mediated endocytosis and/or transc3dosis pathways (5) carrier-mediated route. Note that receptor and carrier proteins in epithelial cells are expressed on both the apical and basolateral surfaces.

Early experiments showed that a transferrin-polycation complex transported bacterial DNA into cells [12]. Ions are taken up by cells as an iron-transferrin complex by receptor-mediated endocytosis. Protamine or poly-lysine ligated by disulfide bonds to transferring and mixed with a lu-ciferase-encoding plasmid may bind the DNA because of the cationic properties of the complex [12]. Subsequently, avian ery-throblasts and human K-562 cells were incubated with the transferrin-polycation peptide-DNA complex, and the complexes were recognized and transported into the cells by receptor-mediated endocytosis and taken up into endosome-Hke intracellular vesicles [12]. Treatment with chloroquine (an agent that affects the endosomal pH) enhanced the uptake considerably. In contrast to other transfection methods, the transfection of cells with transferrin-mediated endocytosis did not cause significant cell death, because of the physiologi-... 

Receptor-Mediated Endocytosis and the Sorting of Internalized Proteins... 

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