Receptor-mediated accumulation

Calcium Channel Blockers. Because accumulation of calcium is one of the facets of the mote involved process leading to atherosclerosis, it would foUow that the antihypertensive calcium channel blockers might be effective in preventing atheroma. Both verapamil (Table 1) and nifedipine (Table 3) have been shown to stimulate the low density Upoprotein (LDL) receptor (159). This specific receptor-mediated pathway could theoretically improve Upid metaboUsm in the arterial wall, and thereby prove antiatherogenic. These effects have been proven in animals. 

BA Kamen, A Capdevile. (1986). Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci USA 83 5983-5987. 

The H2 receptor is the second class of HA receptors. This is another G-protein-coupled receptor but, unlike the Hi receptor, the H2 receptor is coupled to adenylyl cyclase via the GTP-binding Gs protein (Hill et ah, 1997). Encoded by an intronless gene and located on human chromosome 5, the H2 receptor is made up of c. 358 amino acids (Gantz et ah, 1991 Traiffort et ah, 1995). Activation of the H2 receptor causes an accumulation of cAMP and activation of protein kinase A that eventually leads to the activation of cyclic-AMP-response element (CRE)-binding protein (CREB) (Hill et ah, 1997). In neurons, the H2 receptor mediates its excitatory effects by blocking the Ca2+-dependent K+ channel (Haas Konnerth, 1983). 

The human LDL complex delivers cholesterol to cells by receptor-mediated, clathrin-mediated endocytosis. LDL is used to follow the lysosomal directed pathway. Once internalized, LDL dissociates from its receptor and ultimately accumulates in the lysosomes (111). 

Adenosine deaminase catalyzes the hydrolytic deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyinosine respectively. Inhibition of adenosine deaminase leads to an accumulation of its substrates which results in adenosine receptor-mediated effects. Most inhibitors are not reported to have antinociceptive properties, but 2 -deoxycoformycin was proven to have an inhibitory effect on pain transmission (Poon and Sawynok, 1999), and Fujisawa Pharmaceuticals claim adenosine deaminase inhibitors to be active against chronic pain. 

Figure 15.4 Mechanisms of apoptosis induction by resveratrol. Resveratrol selectively induces apoptosis in various cancer cells in culture by several mechanisms including activation of death receptor-mediated signaling, mitochondria-dependent cytochrome c release and caspase activation, induction of p53 and p53-regulated proapototic genes, activation of MAP kinase-mediated p53 phosphorylation, blockade of Akt-mediated cell survival pathways, and accumulation of intracellular ceramide level.

Apart from attaching MRI contrast agents to the cell surface, cell labeling may also be achieved by using cell uptake processes. Endocytosis, whether receptor mediated or not, and phagocytosis are mechanisms that maybe considered and that could lead to accumulation of a magnetic label inside the cell. Provided the... 

Specifically, the data reviewed in Chapters 12 and 13 indicate that LCM are rapidly removed from the circulation by the tumor the maximum accumulation of LCM in the tumor area occurs within the first 30 min after administration (ref. 531). These rapid kinetics for LCM uptake are quite consistent with the well-documented kinetics long-known for the LDL receptor-mediated endocytic pathway (ref. 616). For example, Goldstein et al. (ref. 643) reported that LDL-ferritin bound to coated pits at 4°C is rapidly internalized when fibroblasts in tissue culture are warmed to 37°C. In this uptake process, the coated pits invaginate to form coated endocytic vesicles. After 5 to 10 min at 37°C, LDL-ferritin is observed in lysosomes as the result of their fusion with the incoming coated vesicles (ref. 643). The rapid sequence of events visualized in electron micrographs precisely parallels biochemically-derived data on the rapid uptake and degradation of radiolabeled LDL (ref. 644,645). 

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