Coated pit

Fig. 17. The receptor-internalization process via a coated pit in which receptors are internalized and processed in a multistep pathway before being recycled...

Arrestins act as adaptor proteins that bind to phos-phorylated G protein-coupled receptors (GPCR) and link the receptors to clathrin-coated pits. (3-Arrestins are essential in the internalization of many GPCRs. 

Caveolae are invaginations of the plasma membrane. They contain the protein caveolin and are rich in certain phospholipids. Similar to coated pits, they bud off internally forming endocytic vesicles. Caveolae play an important role in the internalization of certain cell surface receptors. 

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. 

Clathrin-coated Pits Clathrin-coated Vesicle CLC... 

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).

As an example, the low-density lipoprotein (LDL) molecule and its receptor (Chapter 25) are internalized by means of coated pits containing the LDL receptor. These endocytotic vesicles containing LDL and its receptor fuse to lysosomes in the cell. The receptor is released and recycled back to the cell surface membrane, but the apoprotein of LDL is degraded and the choles-teryl esters metabolized. Synthesis of the LDL receptor is regulated by secondary or tertiary consequences of pinocytosis, eg, by metabolic products—such as choles-... 

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. 

Cvejic et al. [133] and Trapaidze et al. [134] have reported that the C-terminus of the 8 receptor is essential for the internalization and downregulation of the receptors. Truncation of the 8 receptor attenuates receptor internalization. Residue Thr353 seems to be selectively involved in the internalization of the receptor, since mutation of this amino acid blocks the internalization process. Recent studies by Chu et al. [135] not only confirm the role of the C-terminus in internalizing the 8 receptor but have shown that clathrin-coated pits are involved in the internalization since a K44I mutant of dynamin I blocks the rapid internalization of the 8 receptor. These studies have identified a structural basis for the differential regulation of the three opiate receptors. 

FIGURE 1-18 A typical desmosome (d) and gap junction (g) between two ependymal cells. Microvilli and coated pits (arrows) are seen along the cell surface. X35,000. 

Clathrin-coated vesicles mediate transport from the Golgi apparatus to endosomes, and from the plasma membrane to endosomes. A multi-subunit protein, clath-rin, constitutes the major protein of this vesicle type (see Ch. 2). Clathrin is composed of three large and three small polypeptide chains, which assemble to form a triskelion (Fig. 9-2). Regulatory mechanisms control the assembly and formation of a convex, polyhexa-pentagonal basketlike structure by these triskelions [5], This structure is responsible for the formation of coated pits on the cytosolic face of plasma membranes. 

Extracellular ligands (hormones, neurotrophins, carrier protein, adhesion molecules, small molecules, etc.) will bind to specific transmembrane receptors. This binding of specific ligand induces the concentration of the receptor in coated pits and internalization via clathrin-coated vesicles. One of the best studied and characterized examples of RME is the internalization of cholesterol by mammalian cells [69]. In the nervous system, there are a plethora of different membrane receptors that bind extracellular molecules, including neurotrophins, hormones and other cell modulators, being the best studied examples. This type of clathrin-mediated endocytosis is an amazingly efficient process, capable of concentrating... 

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