Internalisation receptor

Fig. 5.4 Endocytosis of GPCRs mediated by GRKs, arrestins and clathrin-coated pits. Receptor phosphorylation mediates recruitment of arrestins from the cytoplasm, the arres-tin interaction with other adaptotor proteins, and promotes receptor endocytosis by clathrin-coated pits. Internalised receptors may be sorted into a rapid recycling pathway, or to a degradative pathway into the lysosomes...

Heterologous desensitisation refers to the desensitisation of the response to one agonist by the application of a different agonist. For example, desensitisation of a response to adrenaline by application of 5-HT is mediated by protein kinase A or protein kinase C because these kinases can phosphorylate receptors which are not occupied by agonist. Phosphorylation disrupts the receptor-G-protein interaction and induces the binding of specific proteins, arrestins which enhance receptors internalisation via clathrin-coated pits. Thus desensitisation of G-protein-coupled receptors results in a decrease in the number of functional receptors on the cell surface. 

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

Lorenzi, I, von Eckardstein, A, Cavelier, C, Radosavljevic, S, and Rohrer, L, 2008. Apolipoprotein A-I but not high-density lipoproteins are internalised by RAW macrophages Roles of ATP-binding cassette transporter A1 and scavenger receptor BI. JMolMed 86, 171-183. 

The above procedures imply that (1) there is only a single type of site (2) binding occurs only to the transporter site (usually not the case for trace metals), and (3) the internalisation flux is negligible for the equilibration times that are employed [197,198], These conditions are rarely fulfilled for metal transporters. The interpretation of Scatchard plots is especially ambiguous in the presence of several independent sites. On the other hand, in the biomedical literature, where nonspecific adsorption is generally not a problem, values of 104 to 106 carriers per cell (ca. 10-13 to 10 11 carriers cm-2 of cell surface area), with even lower numbers determined for some receptors (e.g. haematopoetic growth factor [199]), are typically reported. 

Figure 22.10 Reverse cholesterol transfer. High density lipoprotein (HDL) collects cholesterol from cells in various tissues/ organs the complex is then transported in the blood to the liver where it binds to a receptor on the hepatocyte, is internalised and the cholesterolis released into the hepatocyte. This increases the concentration in the liver cells which then decreases the synthesis of cholesterol by inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG-CoA synthase. The cholesterol is also secreted into the bile or converted to bile acids which are also secreted into the bile, some of which is lost in the faeces (Chapter A).

Receptor desensitisation, initiated by phosphorylation of the receptor, can be subsequently followed by receptor internalisation via multiple methods including clathrin-coated pits and/or lipid rafts/caveolae. Clathrin-coated pits are specialized regions of the cell surface that mediates the internalisation of the most of GPCRs to endosomes. Lipid rafts are planar domains in cell membranes that are enriched in specific lipid and proteins with an high content of cholesterol and glycosphingolipid (Chini and Parenti 2004). Caveolae are flask-shaped invaginations located at or near the plasma membrane and are considered a non-planar subfamily of lipid rafts (Ferguson 2001 Chini and Parenti 2004). 

Growth factors are active at very low concentrations, i.e. about 1 pM. They exert their effect by binding to specific cell surface receptors with very high affinity. Related factors show lower affinity for the receptors of other members of the group. Following interaction with its receptor, the growth factor is internalised and transported via endocytotic vesicles to the lysosomal compartment where... 

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