Endocytosis, and Lysosomes

Klemm AR, Young D, Lloyd JB (1998) Effects of polyethyleneimine on endocytosis and lysosome stability. Biochem Pharmacol 56 41 16... 

One of the mechanisms of active reabsorption is endocytosis. Fluid phase endocytosis consists of the incorporation of fluid and solutes in vesicles formed at the base of the brush border membrane of the proximal tubular cells (Figure 1). A more efficient absorptive endocytosis involves first binding of a drug, such as the cationic aminoglycoside and/or may be cadmium [30, 31], to a carrier (phosphatidyhnositol) located in the luminal membrane of the wall of the pinocytotic vesicle occurs followed by endocytosis and lysosomal fusion [32, 33]. 

Other lipoproteins and from cell membranes and converts it to cholesterol esters by the lecithin.-cholesterol acyltransferase (LCAT) reaction. Then HDL either directly transports cholesterol and cholesterol esters to the liver or transfers cholesterol esters to other lipoproteins via the cholesterol ester transfer protein (CETP) Ultimately, lipoprotein particles carry the cholesterol and cholesterol esters to the liver, where endocytosis and lysosomal digestion occur. Thus, reverse cholesterol transport (i.e., the return of cholesterol to the liver) is a major function of HDL. 

Fig. 43.10. Synthesis of the thyroid hormones (T3 and T4). The protein thyroglobulin (Tgb) is synthesized in thyroid follicular cells and secreted into the colloid, lodination and coupling of tyrosine residues in Tgb produce T3 and T4 residues, which are released from Tgb by pinocytosis (endocytosis) and lysosomal action. The coupling of a monoiodotyrosine with a diiodotyrosine (DIT) to form triiodothyronine (Tj) is not depicted here.

Kuranda, M.J. Aronson, N.N. Jr. Receptor-Mediated Endocytosis and Lysosomal Degradation of Asialoglycoproteins by the Liver. In Lysosomes Their Role in Protein Breakdown Glaumann, H. Ballard F.J., eds.. Academic Press, Inc., London, 1987 pp 241-282. 

The geometry of the particles could drastically change their properties. Recent findings indicate that the shape could influence the cellular uptake, endothelial targeting in the vasculature, the rate of endocytosis and lysosomal transport within endothelial cells [50, 51]. Hence, capsules templated on specifically shaped particles would be beneficial for certain applications. Furthermore, the flexibility of the polyelectrolyte molecules allows reproducing of the template shape after removal of the solid core [52-54]. CaC03 particles of different shape (spherical, elliptic, and cubic) have been used for fabrication of polyelectrolyte capsules, which were found to replicate the shape of the initial particles [55]. The properties of microcapsule shells assembled on cubic CdC03 particles were compared to the same shells assembled on spherical silica [56]. 

Ubiquitination reaction is reversible like phosphorylation until the ubiquitinated protein is committed to degradation by the proteasome. The reversibility is less clear with respect to endocytotic degradation, that is, internalization of plasma membrane proteins through endocytosis and their degradation through the lysosome. 

A process similar to endocytosis occurs in the reverse direction when it is known as exocytosis (Figure 5.11). Membrane-bound vesicles in the cytosol fuse with the plasma membrane and release their contents to the outside of the cell. Both endocytosis and exocytosis are manifestations of the widespread phenomenon of vesicular transport, which not only ferries materials in and out of cells but also between organelles, e.g. from the endoplasmic reticulum to the Golgi and then to the lysosomes or to the plasma membrane for secretion (Chapter 1). Many hormones are also secreted in this way, as are neurotransmitters from one nerve into a synaptic junction that joins two nerves (Chapters 12 and 14). 

After interaction of the aforementioned carriers with specific receptors, the carrier is then taken up by endocytosis and transported intracellularly to acidified endosomes and lyso-somes.The carrier is proteolytically degraded in the lysosomes and if a drug is coupled to the carrier, it is then released to diffuse into the cytoplasmic compartment. 

There are four main compartments a soluble macromolecule can enter the central compartment (blood and lymphatic system), interstitium, intestinal lumen, and lysosomes [100, 101]. Minor compartments are primary urine, liquor, bile, etc. There is no experimental evidence that clearly indicates the penetration of synthetic macromolecules into the cytoplasm, i.e, into the intracellular compartment (inside the cell but outside the endosomes or lysosomes) [101]. The movements of soluble macromolecules between body compartments have been extensively reviewed [14, 20,100-104] and will not be covered in detail here. We shall concentrate on the discussion of main factors influencing the movement of soluble macromolecules when administered into the bloodstream. Depending on the structure and molecular weight distribution, part of the polymeric molecules are excreted in the urine. Simultaneously, the macromolecules are cleared from the bloodstream by endocytosis. It is important to note that nonspecific capture of soluble macromolecules by the specialized cells of the reticuloendothelial system is generally much less (orders of magnitude) when compared to vesicular carriers of a comparable structure. 

The liver eliminates proteins on first pass after oral administration and on each pass of hepatic blood flow. Hepatocytes, Kupffer cells, adipocytes, and endothelial cells can all be involved in proteolysis (Figure 5.6). Proteolysis can occur in lysosomes after endocytosis of a protein and lysosomal fusion. Endocytosis of a protein may be a nonspecific or receptor-mediated process. Proteolytic products are eliminated from the liver through biliary excretion, and subsequently digested further in the intestinal tract. 

Several serpentine receptors—including the E> adrenoceptor if it is persistently activated—instead traffic to lysosomes after endocytosis and are degraded. This process effectively attenuates (rather than restores) cellular responsiveness, similar to the process of down-regulation described above for the epidermal growth factor receptor. Thus, depending on the particular receptor and duration of activation, endocytosis can contribute to either rapid recovery or prolonged attenuation of cellular responsiveness (Figure 2-12). 

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